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  5. 基于2000例非小细胞肺癌电子病历数据的研究方向探索

基于2000例非小细胞肺癌电子病历数据的研究方向探索

深度研究匿名用户发表于 2025年09月17日 13:191阅读
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1. 临床特征与流行病学特征分析

1.1 基线特征分布研究

非小细胞肺癌（NSCLC）患者的基线特征分布是理解疾病表型和后续研究的基础。通过对2000多例电子病历数据的统计分析，可以深入揭示中国NSCLC患者群体的独特临床特征。

年龄与性别分布： 对患者年龄进行统计分析，通常会观察到NSCLC在中老年人群中高发。例如，有研究显示SMARCA4缺陷型NSCLC患者与年龄较大相关 1。性别分布方面，虽然总体发病率男性高于女性，但女性非吸烟NSCLC患者比例较高，尤其在腺癌中更为常见 23。对本队列数据进行分析，可明确患者的年龄中位数、年龄段分布以及男女比例，并可进一步探讨不同病理亚型（如腺癌、鳞癌）在年龄和性别构成上的差异。

吸烟史： 吸烟史是非小细胞肺癌重要的危险因素。研究表明，吸烟与鳞状细胞癌的关联性更强，而非吸烟者中腺癌更常见 23。在队列中，需详细统计吸烟者的比例、平均吸烟量（包年数）及戒烟时长。同时，应区分从不吸烟者、既往吸烟者和当前吸烟者，并分析吸烟状态与肿瘤组织学类型（腺癌、鳞癌等）以及分子突变（如EGFR突变在非吸烟者中更为常见 3）之间的关联。例如，有研究发现吸烟史与SMARCA4缺陷型NSCLC显著相关 1，且吸烟通过HIF-1α-METTL3-mA/CDK2AP2通路促进NSCLC进展，导致肿瘤恶性程度更高 4。此外，既往吸烟史或当前吸烟史的患者相较于从不吸烟者，其总生存期（OS）更短，尤其在早期疾病患者中尤为显著 5。

ECOG体力状况评分： ECOG（Eastern Cooperative Oncology Group）体力状况评分是评估患者整体健康状况和预后的重要指标，通常为0-5分。评分越高，患者体力状况越差。在NSCLC患者中，ECOG评分直接影响治疗选择和预后 6。对2000多例数据进行分析，可统计ECOG 0-1分、2分及以上患者的比例，并进一步探讨不同ECOG评分患者在年龄、合并症、疾病分期等方面的差异。例如，有研究发现ECOG PS为2分的晚期NSCLC患者，其免疫治疗的疾病控制率、无进展生存期和总生存期均显著低于ECOG PS为0-1分的患者，尽管不良事件发生率无显著差异 6。

病理类型分布： 非小细胞肺癌主要分为腺癌、鳞状细胞癌和大细胞癌等。不同病理类型在分子特征、治疗反应和预后上存在显著差异。本研究应统计腺癌、鳞癌及其他少见病理类型的比例。例如，在芬兰的一项研究中，65%的NSCLC患者为腺癌，29%为鳞状细胞癌 7。MET外显子14跳跃突变在腺癌或非鳞状亚组中的中位频率为2.4%，而在肉瘤样癌中高达12.0% 8。此外，有研究指出腺癌通常比鳞状细胞癌具有更高的免疫浸润程度 9。

合并症： 合并症对NSCLC患者的治疗耐受性及生存结局有重要影响。需对常见合并症（如高血压、糖尿病、慢性阻塞性肺疾病COPD、心脏病等）的发生率进行统计，并分析合并症数量或类型与患者基线特征（如年龄、ECOG评分）及疾病预后的关联。例如，有研究显示合并症较多的患者在接受治疗时可能面临更多挑战 10。

通过对上述基线特征的详细分析，不仅可以勾勒出本研究队列的整体画像，还能为后续深入探讨预后影响因素、治疗模式优化以及生物标志物研究奠定基础。

2. 预后影响因素挖掘与风险预测模型构建

2.1 单因素预后分析

在非小细胞肺癌（NSCLC）的临床研究中，单因素预后分析是识别与患者生存结局（总生存期 OS、无进展生存期 PFS）相关的重要步骤。通过对电子病历数据的深度挖掘，可以利用Kaplan-Meier生存曲线直观展示不同临床变量对患者生存时间的影响，并运用Log-rank检验评估其统计学显著性。

疾病分期对预后的影响： 肿瘤-淋巴结-转移（TNM）分期系统是评估NSCLC预后的最重要指标之一 11。一般来说，疾病分期越晚，患者的生存期越短 12。针对2000例电子病历数据，可以按照国际肺癌研究协会（IASLC）推荐的TNM分期标准，将患者划分为不同分期组（如IA、IB、IIA、IIB、IIIA、IIIB、IIIC、IVA、IVB期）。然后，绘制各分期组的Kaplan-Meier生存曲线，并计算中位OS和PFS。预期结果将显示，早期（I-II期）NSCLC患者的生存率显著高于晚期（III-IV期）患者 13。例如，有研究表明，在某健康区域，I期和II期肺癌患者的中位生存期为57个月（约4.75年），而晚期患者则显著缩短 13。此外，肿瘤大小（T分期）、淋巴结转移（N分期）和远处转移（M分期）的增加，均与更差的预后相关 14。

治疗方式对预后的影响： NSCLC的治疗方式多样，包括手术、放疗、化疗、靶向治疗和免疫治疗等。对不同治疗方案的疗效进行单因素分析至关重要。

  • 手术治疗： 对于早期NSCLC患者，手术是主要的根治性治疗手段，通常能获得较好的长期生存 12。在数据集中，可以比较接受手术切除的患者与未接受手术患者的生存差异。例如，对于I期和II期NSCLC患者，接受手术治疗者的生存率更高 13。即使是部分可切除的IIIA期患者，术前新辅助治疗结合手术也能显著改善事件无进展生存期和总生存期 15。
  • 放疗： 对于不适合手术的早期NSCLC患者，根治性放疗（如立体定向放疗SABR）可以显著延长生存期 1617。对于局部晚期NSCLC，放化疗是标准治疗。可以分析接受不同放疗剂量或方案（如根治性放疗、姑息性放疗）患者的生存结局。
  • 化疗： 化疗常作为晚期NSCLC的一线或二线治疗。可以对比接受化疗与未接受化疗患者的生存情况。
  • 靶向治疗： 针对EGFR、ALK、ROS1等驱动基因突变的靶向治疗极大地改善了相应患者的预后。如果电子病历包含分子检测数据，可以分析有无驱动基因突变以及是否接受靶向治疗对生存的影响。例如，对于EGFR突变的NSCLC患者，靶向治疗的无进展生存期显著优于传统化疗。
  • 免疫治疗： 以PD-1/PD-L1抑制剂为代表的免疫治疗在PD-L1高表达或特定基因突变（如TMB高）的晚期NSCLC患者中显示出显著疗效。如果数据允许，可分析接受免疫治疗患者的生存情况。

合并症对预后的影响： 患者的合并症状况是影响治疗耐受性和预后的重要因素。可以计算患者的Charlson合并症指数（CCI）或其他合并症评分，并将其作为分类变量进行生存分析。研究显示，合并症数量或严重程度的增加通常与较差的预后相关 17。例如，慢性阻塞性肺疾病（COPD）、心脏病、糖尿病等常见合并症可能增加治疗风险，影响患者的生存时间。特别是在不适合手术的早期NSCLC患者中，Charlson合并症指数是总生存期的重要预测因子 17。

其他临床变量： 此外，还可以进行其他临床变量的单因素分析，例如：

  • 年龄： 通常认为年轻患者预后相对较好，但高龄患者在接受规范治疗后仍能获益 13。
  • 性别： 有研究表明女性NSCLC患者的预后优于男性，即使在调整多项预后因素后，这种差异依然存在 18。
  • 病理类型： 腺癌和鳞癌在治疗反应和预后上存在差异。虽然两者都被归为NSCLC，但分子生物学和临床表现差异显著 19。
  • 肿瘤位置： 部分研究表明，位于上叶的NSCLC肿瘤可能与更好的5年生存率相关 20。

通过这些单因素分析，可以初步筛选出与NSCLC患者生存结局显著相关的临床和治疗特征，为后续的多因素分析和预测模型构建提供重要依据。

2.2 多因素预后模型开发

在单因素分析的基础上，为了更全面地理解非小细胞肺癌（NSCLC）患者的预后影响因素并构建更准确的预测工具，多因素预后模型开发至关重要。本研究将采用Cox比例风险模型来筛选独立的预后因素，并在此基础上构建列线图（Nomogram）预测模型，以期为临床实践提供个体化的生存预测。

Cox比例风险模型的应用：
Cox比例风险模型是一种常用的多变量生存分析方法，它能够同时评估多个预后因素对生存时间的影响，并调整混杂因素。在对2000例NSCLC电子病历数据进行分析时，将纳入在单因素分析中显示出统计学意义（如p值<0.05）的临床变量，以及具有潜在临床意义但单因素分析未达显著水平的变量（例如：吸烟史、ECOG评分、TNM分期、病理类型、治疗方式、是否发生脑转移或肝转移等）。模型将识别出在其他变量调整后仍独立影响患者总生存期（OS）或无进展生存期（PFS）的因素。每个独立预后因素将获得一个风险比（Hazard Ratio, HR）和相应的95%置信区间（Confidence Interval, CI），HR值大于1表示该因素增加死亡或疾病进展的风险，小于1则表示降低风险。例如，一项针对晚期NSCLC患者的预后模型开发中，性别、病理类型、ECOG评分、肝转移、血红蛋白水平、白细胞计数、腹膜转移、皮肤转移和淋巴细胞百分比等被确定为独立的预后因素 21。另一项研究则识别出6个基因表达谱（ABCC4, ADRBK2, KLHL23, PDS5A, UHRF1, ZNF551）构建的风险评分是NSCLC的独立预后因素 22。

Nomogram预测模型的构建：
列线图（Nomogram）是一种直观且实用的图形化预测工具，它将复杂的Cox回归模型结果转化为易于理解和使用的图表，允许临床医生根据患者的具体特征快速估计其在特定时间点（如1年、3年、5年）的生存概率。构建Nomogram的步骤如下：

  1. 变量选择： 基于Cox回归分析中筛选出的独立预后因素，作为构建Nomogram的关键变量。这些变量通常包括人口学特征、临床病理指标、治疗信息以及分子生物学标志物等。例如，有研究将年龄、性别、分化程度、T分期、N分期和M分期等纳入非小细胞肺癌腺泡型腺癌患者的OS预测Nomogram 23。另一项研究则通过影像组学和临床特征构建Nomogram来预测新辅助免疫化疗后的主要病理缓解（MPR）24。
  2. 模型训练： 利用训练集数据，通过逻辑回归或Cox回归等方法，确定每个预测变量的权重。这些权重在Nomogram上通过每个变量对应的点数（points）来表示。
  3. 图形化呈现： 在Nomogram上，每个变量都有一条刻度线，线上对应不同的点数。患者的各项特征值在各自的刻度线上找到对应点数，将所有点数相加得到总点数。再通过总点数对应下方的风险刻度，即可读取到预测的生存概率。例如，对于膀胱癌伴肺转移患者的OS预测Nomogram，纳入了诊断年龄、原发部位、组织学类型、原发灶手术、化疗、骨转移和肝转移等因素 25。
  4. 模型内部验证： 为了确保模型的稳定性，通常会采用自助法（Bootstrap resampling）进行内部验证，以评估模型在未见过的数据上的表现。

模型效能评估与验证：
Nomogram模型的效能评估是其临床应用价值的关键。主要通过以下指标进行验证：

  1. 一致性指数（C-index）： C-index是评估Cox回归模型区分度（discrimination）的常用指标，取值范围为0.5到1。C-index为0.5表示模型预测能力与随机猜测无异，而1表示完美预测。C-index越高，说明模型区分高风险和低风险患者的能力越强。例如，有研究在验证NSCLC预后模型时使用了C-index来评估模型的符合度 26。一项基于影像组学和剂量组学预测放射性肺炎的模型，其C-index在训练集和外部验证集分别达到了0.793和0.855 27。
  2. 校准曲线（Calibration Curve）： 校准曲线用于评估模型的校准度（calibration），即模型的预测结果与实际观察结果的一致性。曲线图的X轴代表Nomogram预测的生存概率，Y轴代表实际观察到的生存概率。如果预测与实际一致，则校准曲线应尽可能接近45度对角线。通过绘制不同时间点（如1年、3年、5年）的校准曲线，可以直观地评估模型预测的准确性。
  3. 决策曲线分析（Decision Curve Analysis, DCA）： DCA是一种评估预测模型临床实用性的方法。它通过计算不同阈值下的净获益（Net Benefit）来衡量模型在临床决策上的价值。如果模型的DCA曲线在较宽的阈值范围内高于“全治疗”和“全不治疗”策略的曲线，则表明该模型具有更好的临床决策价值 2428。

通过上述多因素预后模型开发和严格的内部验证，本研究旨在构建一个基于电子病历数据的、高度个体化的NSCLC预后预测Nomogram，为临床医生提供更精准的预后评估工具，从而优化患者管理和治疗方案的选择。

3. 治疗模式优化与疗效差异评估

非小细胞肺癌（NSCLC）的治疗模式近年来取得了显著进展，从传统的化疗、放疗发展到精准靶向治疗和免疫治疗，极大地改善了患者的预后。对2000例电子病历数据的分析，将有助于揭示真实世界中不同治疗方案的应用规律、疗效差异以及优化潜力，为临床实践提供更具针对性的循证依据。

3.1 治疗方案选择规律分析

通过对电子病历数据的深入分析，可以全面描绘非小细胞肺癌患者在不同疾病阶段、不同基线特征下所接受的治疗方案选择规律。这包括统计各种治疗手段（手术、放疗、化疗、靶向治疗、免疫治疗）的应用比例，以及探讨序贯治疗和联合治疗模式的分布特征。

手术治疗的应用：
手术切除是早期（IB-IIIA期）NSCLC的主要根治性手段。在电子病历数据中，需要统计接受手术治疗的患者比例，并进一步分析手术方式（如肺叶切除、全肺切除、微创手术与开放手术等）的分布。重要的是，应结合患者的TNM分期、肿瘤大小、淋巴结状态、肺功能以及合并症等因素，评估手术适应症的把握程度。例如，对于可切除的IIIA期NSCLC患者，新辅助放化疗或新辅助化疗联合免疫治疗后再进行手术，能显著提高R0切除率，并带来更好的事件无进展生存期和总生存期 2930。研究还可以探讨术前新辅助治疗（如新辅助化疗联合免疫治疗）的实施比例，以及与传统单纯手术相比的疗效差异。例如，有研究发现新辅助化疗联合免疫治疗在可切除NSCLC中，病理完全缓解率和主要病理缓解率显著提高 29。此外，患者术前的体力状况和呼吸功能评估（如FEV1）也是决定能否手术的重要考量，术前预康复训练与术后康复训练在功能恢复方面具有相似效果 31。

放疗的应用：
放射治疗在NSCLC治疗中占据重要地位，包括根治性放疗（常用于不适合手术的早期患者或局部晚期患者）、辅助放疗（术后放疗）和姑息性放疗（用于缓解症状）。

  • 根治性放疗： 针对不适合手术的早期NSCLC患者，立体定向放疗（SBRT）是一种有效的根治性选择。对于局部晚期（III期）不可切除的NSCLC患者，同步放化疗是标准治疗方案 32。分析数据时，需统计接受根治性放疗患者的比例，并区分是否联合化疗或免疫治疗，同时关注放疗剂量、分割方式以及靶区范围。
  • 辅助放疗： 对于部分术后淋巴结阳性（N1/N2）的患者，术后辅助放疗可能改善局部控制。需统计接受辅助放疗的患者比例，并分析其指征。
  • 姑息性放疗： 用于缓解疼痛、出血、气道阻塞等症状。这类患者的比例及其放疗方案也值得关注。

化疗的应用：
化疗是NSCLC治疗的基石之一，贯穿于新辅助、辅助、同步放化疗以及晚期姑息治疗的各个阶段。

  • 新辅助/辅助化疗： 统计术前新辅助化疗和术后辅助化疗的比例。
  • 同步放化疗： 针对局部晚期不可切除NSCLC，同步放化疗优于序贯放化疗 32。
  • 晚期一线/二线化疗： 分析晚期NSCLC患者接受化疗的比例，以及常用化疗方案（如铂类双药方案、多西他赛等）的分布。

靶向治疗的应用：
靶向治疗是精准医学在NSCLC领域的典范。对于具有特定驱动基因突变（如EGFR突变、ALK重排、ROS1融合等）的患者，靶向药物能显著提高疗效并降低毒性 33。

  • 突变检测比例： 首先应统计电子病历中分子检测的比例，以及各类驱动基因突变的阳性率。这反映了临床实践中基因检测的普及程度。
  • 靶向药物应用： 分析携带EGFR、ALK、ROS1等突变患者中，接受相应靶向治疗（如EGFR-TKI，如奥希替尼；ALK抑制剂，如阿来替尼等）的比例。例如，奥希替尼已获批用于EGFR突变NSCLC患者的辅助治疗，显著延长了无病生存期 34。阿来替尼在ALK阳性NSCLC患者中也显示出优于化疗的疗效 35。
  • 序贯治疗： 某些情况下，患者可能经历多线靶向治疗，例如EGFR突变患者在第一代TKI耐药后接受第三代TKI（如奥希替尼）治疗 36。分析这种序贯治疗模式的分布和疗效。

免疫治疗的应用：
免疫检查点抑制剂（ICI），特别是PD-1/PD-L1抑制剂，彻底改变了晚期NSCLC的治疗格局 37。

  • PD-L1表达检测： 统计PD-L1表达检测的比例以及PD-L1不同表达水平（如TPS≥50%、1%-49%、<1%）的分布。PD-L1表达水平是预测免疫治疗疗效的重要生物标志物 38。
  • 免疫治疗应用： 分析接受PD-1/PD-L1抑制剂（如帕博利珠单抗、纳武利尤单抗等）治疗的患者比例。
  • 联合治疗与序贯治疗： 统计免疫治疗与其他疗法（如化疗、靶向治疗）联合或序贯使用的比例。例如，先前的研究表明，对于局部晚期NSCLC，新辅助化疗联合免疫治疗可能优于单纯新辅助化疗 29。此外，免疫治疗与靶向治疗的联合或序贯应用也日益受到关注 3940。纳武利尤单抗（Nivolumab）与多西他赛（Docetaxel）在晚期鳞状NSCLC中相比，显示出更好的总生存率、缓解率和无进展生存期，且与PD-L1表达水平无关 41。

通过对上述各项治疗方案选择规律的详细分析，能够洞察真实世界中NSCLC的治疗现状，揭示不同治疗路径的偏好性，并为后续的疗效差异评估和治疗模式优化提供数据支持。

3.2 不同治疗方案的疗效对比

在详细分析了非小细胞肺癌（NSCLC）患者的治疗方案选择规律后，下一步关键是评估这些不同治疗模式对患者临床结局的影响。本节将重点比较各种治疗方案（包括手术、放疗、化疗、靶向治疗、免疫治疗及其联合模式）在客观缓解率（Objective Response Rate, ORR）、疾病控制率（Disease Control Rate, DCR）和生存结局（总生存期 Overall Survival, OS；无进展生存期 Progression-Free Survival, PFS）上的差异。鉴于真实世界数据中存在的选择偏倚和混杂因素，我们将探讨如何利用倾向得分匹配（Propensity Score Matching, PSM）或其他统计方法来控制这些偏倚，以获得更可靠的疗效对比结果，并探索不同亚组患者（如EGFR突变阳性、PD-L1高表达）的优势治疗路径。

疗效指标的定义与计算：

  • 客观缓解率 (ORR)： 定义为达到完全缓解（Complete Response, CR）和部分缓解（Partial Response, PR）的患者比例。
  • 疾病控制率 (DCR)： 定义为达到CR、PR和疾病稳定（Stable Disease, SD）的患者比例。
  • 无进展生存期 (PFS)： 从随机分组或治疗开始至疾病进展或因任何原因死亡的时间。
  • 总生存期 (OS)： 从随机分组或治疗开始至因任何原因死亡的时间。

不同治疗方案的疗效对比分析：
本研究将基于电子病历数据，对接受不同治疗方案的患者群体进行疗效对比。例如：

  1. 手术与放疗的比较： 对于早期可手术的NSCLC患者，手术切除通常是金标准。然而，对于不适合手术的患者，立体定向放疗（SBRT）已成为一种有效的替代方案 42。早期NSCLC的研究表明，SBRT在3年和5年总生存率方面与胸腔镜辅助肺叶切除术（VATS L-MLND）无显著差异，且不良事件发生率较低 42。另一项研究也指出，SBRT与手术相比，急性毒性更低，3个月死亡率更低，但对于预期寿命较长的患者，手术可能带来相对益处 43。本研究可对数据中接受SABR和手术的早期患者进行生存分析和并发症比较。

  2. 化疗、靶向治疗和免疫治疗的比较：

    • 靶向治疗与化疗： 对于携带驱动基因突变（如EGFR突变、ALK重排）的晚期NSCLC患者，靶向治疗的疗效显著优于传统化疗。例如，EGFR-TKI药物能显著延长EGFR突变患者的PFS和OS 44。本研究将比较这些特定突变亚组中接受靶向治疗与化疗患者的ORR、PFS和OS。
    • 免疫治疗与化疗： 免疫检查点抑制剂（ICIs）已成为晚期NSCLC的重要治疗手段。对于PD-L1高表达的患者，免疫单药治疗已成为一线标准。例如，阿替利珠单抗（Atezolizumab）在延长OS方面优于多西他赛（Docetaxel），且疗效与纳武利尤单抗（Nivolumab）相当 45。多项研究也表明，PD-1/PD-L1抑制剂联合化疗在OS和PFS方面优于单纯化疗 46。本研究将评估不同PD-L1表达水平的患者在接受免疫单药、免疫联合化疗或单纯化疗后的疗效差异。
    • 免疫治疗与靶向治疗： 随着免疫治疗的普及，对于同时有驱动基因突变和PD-L1表达的患者，选择靶向治疗还是免疫治疗或联合治疗是一个临床难题。本研究可探索这两类治疗策略的优劣。

  3. 不同联合治疗模式的比较：

    • 新辅助化疗联合免疫治疗： 对于可切除NSCLC，新辅助化疗联合免疫治疗显示出更高的病理完全缓解率和主要病理缓解率，并能显著改善事件无进展生存期和总生存期，即使对于PD-L1表达<1%的患者也能观察到获益 29。本研究可以对比接受不同新辅助方案患者的手术切除率、病理缓解率和长期生存结局。
    • 免疫治疗联合靶向治疗： 针对特定分子亚型，如KRAS突变或HER2突变，探索免疫治疗与新型靶向药物联合的疗效。

倾向得分匹配 (PSM) 控制混杂因素：
由于电子病历数据来源于真实世界，患者特征（如年龄、体力状态、合并症、疾病分期、肿瘤负荷等）在不同治疗组间可能存在不均衡，导致结果偏倚。为减少这种偏倚，本研究将采用倾向得分匹配（PSM）方法：

  1. 计算倾向得分： 使用多变量Logistic回归模型，根据基线特征（如年龄、性别、ECOG评分、吸烟史、TNM分期、病理类型、基因突变状态、PD-L1表达等）预测患者接受某种特定治疗方案的概率，即倾向得分。
  2. 进行匹配： 基于倾向得分，采用1:1或1:N匹配方法（如最近邻匹配、卡钳匹配等），为每个接受研究治疗的患者在对照组中找到特征最相似的患者。匹配后，两个组的基线特征将更加平衡。
  3. 疗效对比： 在匹配后的队列中，再次比较不同治疗方案的ORR、DCR、PFS和OS，以获得更接近随机对照试验的疗效评估结果。例如，在比较放化疗与巩固化疗对III期NSCLC患者生存影响的研究中，就采用了倾向得分匹配来调整混杂因素 47。

亚组分析探索优势治疗路径：
除了总体疗效对比，深入的亚组分析对于指导临床实践至关重要。本研究将根据以下关键特征进行亚组分析，以识别不同治疗方案在特定患者群体中的优势：

  • 分子驱动基因状态： 如EGFR突变、ALK重排、ROS1融合、KRAS突变、MET外显子14跳跃突变等。
  • PD-L1表达水平： PD-L1肿瘤细胞阳性比例（TPS）≥50%、1%-49%、<1%。
  • 组织学类型： 腺癌与鳞癌。例如，Datopotamab Deruxtecan在非鳞状NSCLC患者中显著改善PFS，但在鳞状NSCLC患者中未显示出相似益处 48。
  • 疾病分期和转移模式： 如寡转移NSCLC患者，局部消融治疗（手术或SABR）可能带来PFS和OS的获益 16。
  • ECOG体力状态： 评估体力状态较差（ECOG≥2）的患者是否能从某些治疗中获益。

通过上述多维度、严谨的疗效对比分析，结合PSM等统计学方法控制混杂因素，本研究将为NSCLC的个体化治疗提供有力的真实世界证据，指导临床医生为不同特征的患者选择最优的治疗方案。

4. 生物标志物与临床表型关联研究

随着精准医学的快速发展，生物标志物在非小细胞肺癌（NSCLC）的诊断、治疗选择和预后判断中扮演着越来越重要的角色。通过对2000例电子病历数据的深入挖掘，我们可以系统性地评估现有生物标志物的临床价值，并探索新型临床表型组合，为NSCLC的个体化治疗提供更精确的指导。

4.1 现有生物标志物的临床价值验证

本节将重点分析电子病历数据中常见的驱动基因突变（如EGFR、ALK、ROS1）以及免疫治疗相关生物标志物（如PD-L1表达、TMB）的检测结果分布情况，并评估它们与患者治疗反应和预后的相关性。

1. 驱动基因突变（EGFR/ALK/ROS1等）

  • 突变阳性率统计： 首先，需统计电子病历中各类驱动基因突变的检测比例以及阳性率。在亚洲人群中，EGFR突变在NSCLC（尤其是腺癌）中的发生率显著高于西方人群，例如，一项针对台湾NSCLC患者的研究显示EGFR突变频率远高于TCGA数据中的高加索人群，而KRAS突变频率较低 49。全球范围内，EGFR突变在NSCLC中的流行率为10%至50%不等，亚洲患者的发生率更高 50。ALK重排的发生率约为3%-7% 50，ROS1融合则相对较少，约占1%-2% 50。通过分析本队列数据，可以获得中国特定地域NSCLC患者的真实世界突变谱，并与已发表文献进行比较。
  • 与靶向治疗反应的关联： 对于EGFR突变阳性的患者，EGFR酪氨酸激酶抑制剂（EGFR-TKI）是标准的一线治疗方案，能够显著提高客观缓解率（ORR）和无进展生存期（PFS） 51。类似地，ALK/ROS1重排阳性的患者对相应的抑制剂（如ALK抑制剂、ROS1抑制剂）也显示出卓越的治疗反应。本研究将通过比较有无特定突变且是否接受靶向治疗的患者，评估这些突变对治疗有效率（ORR、DCR）的影响。
  • 与预后的关联： 驱动基因突变状态不仅影响治疗选择，也可能对预后产生独立影响。例如，EGFR突变患者在未接受靶向治疗时，其预后可能与野生型患者存在差异。本研究将分析各类突变状态（包括常见的EGFR、ALK、ROS1以及其他潜在的驱动基因如KRAS、BRAF、MET等）对总生存期（OS）和无进展生存期（PFS）的影响，并通过Kaplan-Meier曲线和Cox回归模型进行验证。

2. PD-L1表达

  • PD-L1表达水平统计： PD-L1（程序性死亡配体1）在肿瘤细胞表面的表达是预测免疫检查点抑制剂（ICI）疗效的关键生物标志物。需要统计电子病历中PD-L1检测的比例，并根据肿瘤细胞阳性比例（TPS）将患者分为高表达（TPS ≥ 50%）、中表达（1% ≤ TPS < 50%）和低表达（TPS < 1%）组。一项全球多中心真实世界研究（EXPRESS研究）显示，在局部晚期或转移性NSCLC患者中，PD-L1 TPS ≥ 50%的患者占22%，TPS ≥ 1%的患者占52% 52。本队列的PD-L1表达分布将反映中国NSCLC患者的真实世界情况。
  • 与免疫治疗反应的关联： PD-L1高表达的NSCLC患者对PD-1/PD-L1抑制剂（如帕博利珠单抗）单药治疗的客观缓解率和生存期均显著提高 5354。本研究将重点分析PD-L1不同表达水平患者接受免疫治疗后的ORR、DCR、PFS和OS，以验证PD-L1作为预测生物标志物的价值。同时，也可以探索PD-L1表达与免疫治疗相关不良事件（irAEs）之间的关系。
  • 与预后的关联： 尽管PD-L1被广泛用作预测免疫治疗反应的生物标志物，但其作为独立预后标志物的价值仍存在争议。部分研究表明，高PD-L1表达可能预示着更差的总体生存，但在接受免疫治疗后，高表达的患者反而获益更大 55。本研究将评估PD-L1表达水平在未接受免疫治疗或接受其他治疗方案患者中的预后价值。

3. 肿瘤突变负荷（TMB）

  • TMB检测数据分析： 肿瘤突变负荷（TMB）是指肿瘤基因组中体细胞非同义突变的总数，高TMB通常与更好的免疫治疗反应相关 5456。本研究将统计电子病历中TMB检测的比例和TMB值的分布。尽管TMB的检测标准化仍面临挑战 54，但高TMB的患者通常预示着对免疫检查点抑制剂的更好反应 56。
  • 与免疫治疗反应的关联： 较高TMB的NSCLC患者通常对免疫检查点抑制剂反应更佳，PFS更长 56。本研究将分析TMB高低与免疫治疗ORR、DCR、PFS和OS之间的关系。
  • PD-L1与TMB的联合评估： 尽管PD-L1和TMB都是预测免疫治疗疗效的生物标志物，但它们之间通常不相关联，且具有独立的预测能力 56。本研究将探索PD-L1表达和TMB联合预测免疫治疗疗效的潜力，例如，同时高PD-L1表达和高TMB的患者是否能获得最佳的临床获益，以及两者在预测不同类型ICI（单药或联合治疗）疗效中的相对重要性。

通过对这些现有生物标志物的全面验证，本研究将为临床医生提供更明确的证据，以指导NSCLC患者的治疗策略选择，尤其是在靶向治疗和免疫治疗时代。

4.2 新型临床表型组合探索

尽管现有的生物标志物（如EGFR突变、PD-L1表达）在非小细胞肺癌（NSCLC）的精准治疗中发挥了重要作用，但肺癌的临床表现和治疗反应仍存在显著异质性。这提示我们，除了单一生物标志物，多种临床和分子特征的组合可能定义出具有独特临床行为和治疗敏感性的患者亚组，即“临床表型”。通过对2000例电子病历数据的聚类分析，可以挖掘潜在的新型临床表型亚组，分析这些亚组间的治疗选择与生存差异，进而提出针对性的管理建议。

聚类分析方法的应用：
聚类分析是一种无监督学习方法，旨在将相似的数据点分组。在NSCLC电子病历数据中，可以将患者视为数据点，其临床特征（如年龄、性别、吸烟史、ECOG评分、TNM分期、病理类型、组织学分级、合并症、分子检测结果、肿瘤标志物水平等）作为特征变量。常用的聚类算法包括层次聚类、K-均值聚类和基于模型的聚类等。例如，有研究通过聚类分析将早期可治愈的NSCLC患者分为具有不同预后的表型，发现即使TNM分期相同，患者的临床进程和结局仍存在显著差异 57。另一项针对小细胞肺癌（SCLC）的研究也利用机器学习方法（如分区围绕中位数聚类）成功识别出7个紧凑且分离良好的预后亚组，这些亚组在绩效状态、乳酸脱氢酶、转移扩散、癌症分期和C反应蛋白等基线特征上存在显著差异 58。

挖掘潜在的临床表型亚组：
通过对大规模电子病历数据进行聚类分析，可以识别出以下几种可能的新型临床表型组合：

  1. “年轻-非吸烟-腺癌-EGFR突变”亚组： 这一群体在中国NSCLC患者中相对常见。他们通常无吸烟史，诊断年龄相对较轻，病理类型多为腺癌，且高比例伴有EGFR敏感突变。该亚组可能对EGFR-TKI治疗反应极佳，但可能伴随特定的耐药机制或转移模式（如脑转移）。深入分析其预后及治疗策略，例如，对于EGFR突变伴脑转移的肺腺癌患者，TKI联合放疗可以显著延长总生存期（OS）和颅内无进展生存期（iPFS） 59。
  2. “老年-多合并症-早期鳞癌”亚组： 这类患者年龄较大，常伴有慢性阻塞性肺疾病（COPD）、心脏病等多种合并症，病理类型多为鳞状细胞癌，且通常无驱动基因突变。对于此类患者，治疗选择可能受合并症限制，耐受性较差。分析其对SBRT或同步放化疗的耐受性及疗效，并探索最佳的治疗强度和支持治疗方案。
  3. “高TMB/PD-L1高表达-免疫治疗敏感”亚组： 这类患者可能具有较高的肿瘤突变负荷（TMB）和/或PD-L1高表达，即使TNM分期较晚，也可能对免疫检查点抑制剂（ICI）表现出持久的响应。研究该亚组的临床病理特征、ICI治疗反应率、PFS和OS，并进一步探索其是否具有特定的免疫微环境特征或共突变模式。例如，有研究通过PET/CT影像组学和临床特征的机器学习模型预测NSCLC的肿瘤免疫图谱，发现高CD8表达组具有更高的免疫评分和激活的免疫通路 60。
  4. “非典型驱动基因突变/耐药基因变异”亚组： 除了常见的EGFR/ALK/ROS1突变，数据中可能包含BRAF、MET、RET等较少见的驱动基因突变，或与耐药相关的基因变异（如EMT表型转化与EGFR抑制剂耐药相关 61）。聚类分析可以帮助识别这些非典型突变患者的临床特征，并分析其对特定靶向药物或联合治疗的响应。
  5. “特定转移模式”亚组： 根据患者初诊时的转移部位（如脑转移、骨转移、肝转移、肾上腺转移等）进行聚类，分析不同转移模式下患者的预后和治疗选择。例如，某些转移模式可能提示预后更差或需要特殊的局部治疗。

分析亚组间治疗选择与生存差异：
在识别出不同的临床表型亚组后，将对每个亚组内的治疗选择进行详细统计，并比较不同治疗方案在该亚组内的疗效（ORR、PFS、OS）和安全性。这有助于回答以下问题：

  • 特定临床表型亚组是否更倾向于选择某种治疗方案？
  • 在特定亚组中，某种治疗方案的疗效是否显著优于其他方案？
  • 是否存在某些亚组对现有治疗方案不敏感，需要探索新的治疗策略？

提出针对性管理建议：
基于聚类分析的结果和亚组间的疗效差异，可以为不同临床表型亚组的NSCLC患者提出个体化的管理建议：

  • 诊断建议： 针对特定亚组，建议更积极地进行某些生物标志物检测，例如对年轻非吸烟腺癌患者进行全面的驱动基因检测。
  • 治疗策略建议： 根据亚组特征，推荐优先考虑的治疗方案（如靶向治疗、免疫治疗、局部治疗或联合治疗），甚至可以提出新的治疗组合方案。
  • 预后预测和随访建议： 不同的临床表型可能具有不同的预后，从而影响随访频率和强度。

通过这种多维度、基于数据的聚类分析，有望超越单一指标的限制，更全面地理解NSCLC的异质性，为实现真正的个体化精准医疗奠定基础。

5. 并发症与合并症的影响机制研究

5.1 治疗相关并发症发生规律

非小细胞肺癌（NSCLC）的治疗在延长患者生存期的同时，也常伴随着一系列治疗相关并发症。这些并发症不仅影响患者的生活质量，还可能导致治疗中断，甚至危及生命。通过对2000例电子病历数据的分析，可以揭示真实世界中各类治疗相关并发症的发生频率，并深入探讨其与治疗方案和患者特征之间的关联。

1. 放射性肺炎 (Radiation Pneumonitis, RP)

放射性肺炎是胸部放疗常见的并发症，其严重程度与放疗剂量、照射体积、同步化疗等因素密切相关。在我们的电子病历数据中，需要统计放射性肺炎的发生率，并根据Common Terminology Criteria for Adverse Events (CTCAE) v5.0标准对其进行分级（G1-G5）。

  • 发生率分析： 研究表明，NSCLC患者接受放疗后，2级及以上放射性肺炎的发生率较高。例如，一项回顾性研究显示，在接受同步放化疗和巩固性度伐利尤单抗治疗的NSCLC患者中，2级及以上放射性肺炎的发生率为30%，其中3级占3%，4级占1%，5级占1% 62。另一项研究则指出，接受免疫治疗后再进行放疗的NSCLC患者，2级及以上放射性肺炎发生率为26.7% 63。本研究将统计队列中接受放疗患者的放射性肺炎发生率，并与文献报道进行比较。
  • 风险因素分析：
    • 放疗剂量和体积： 肺的受照体积（如V20，即接受20Gy或更高剂量照射的肺体积百分比）是放射性肺炎的重要预测因子之一。多项研究证实，V20≥26%显著增加2级以上放射性肺炎的风险 62。此外，总肿瘤体积（GTV）≥21ml和同侧肺V20≥25%也被认为是同步奥莫替尼和胸部放疗后放射性肺炎的风险因素 64。本研究将分析V20、平均肺剂量（MLD）等剂量学参数与放射性肺炎发生的关系。
    • 治疗方案： 同步放化疗通常比单纯放疗有更高的放射性肺炎风险。而免疫检查点抑制剂（ICI）的加入可能增加放射性肺炎的复杂性，表现为免疫相关性肺炎或放射回忆性肺炎（Radiation Recall Pneumonitis, RRP） 65。例如，有研究显示，接受PD-1或PD-L1抑制剂治疗并有放疗史的肺癌患者，放射回忆性肺炎的发生率高达18.8%，且与免疫相关性肺炎（irAEs）相关 65。
    • 患者自身特征： 患者的肺功能（如FEV1）、年龄、吸烟史以及基础肺部疾病（如间质性肺病、COPD）均可能影响放射性肺炎的发生。例如，特发性肺纤维化（IPF）是发生严重放射性肺炎的显著风险因素（OR=48.4），而COPD患者在接受高剂量放疗后，其严重放射性肺炎的风险并未显著增加 66。本研究将细致分析这些患者特征在放射性肺炎发生中的作用。

2. 免疫相关不良事件 (immune-related Adverse Events, irAEs)

随着免疫检查点抑制剂（ICI）在NSCLC治疗中的广泛应用，irAEs成为临床关注的焦点。这些不良事件可累及几乎所有器官系统，最常见的是皮肤、胃肠道、内分泌系统和肺部 67。

  • 发生率与类型： 需要统计队列中接受ICI治疗患者irAEs的总体发生率，以及具体类型的irAEs（如免疫相关性肺炎、甲状腺功能减退、皮疹、结肠炎、肝炎等）的发生频率和分级。例如，阿替利珠单抗治疗的NSCLC患者中，约48.4%发生至少一次irAEs，最常见的是皮疹、肝炎和甲状腺功能减退 67。其中，免疫相关性肺炎（CIP）是特别值得关注的潜在致死性irAEs 68。
  • 发生时间与轨迹： irAEs的发生时间具有异质性，可能在治疗早期出现，也可能在治疗结束后数月甚至更长时间出现 67。对irAEs发生时间（中位时间）进行分析，可以为临床早期识别和干预提供依据。
  • 风险因素分析：
    • ICI种类和联合治疗： 不同ICI药物或联合治疗方案（如ICI+化疗，或双免疫检查点抑制剂）可能导致不同类型和严重程度的irAEs。例如，一项研究指出，接受围手术期度伐利尤单抗（Durvalumab）治疗的NSCLC患者，3-4级不良事件的发生率与安慰剂组相似 69。而接受围手术期特瑞普利单抗（Toripalimab）联合化疗的患者，免疫相关不良事件发生率更高，但3级及以上不良事件、致死性不良事件和导致治疗中断的不良事件发生率与对照组相当 70。
    • 患者自身特征： 年龄、BMI、合并症等因素可能影响irAEs的发生。例如，较高BMI的患者发生任何级别irAEs的风险显著增加，其中肥胖患者发生3-4级irAEs的风险更高 71。此外，有研究发现重度COPD患者接受免疫治疗后，irAEs发生率显著高于无COPD或轻中度COPD患者 72。
    • PD-L1表达： 一些报道提示PD-L1高表达可能与免疫介导的腹泻和结肠炎等irAEs的发生相关 73。
  • 特殊irAEs： 除了常见类型，还需关注罕见但严重的irAEs，例如再生障碍性贫血等 74。

3. 其他治疗相关并发症

  • 化疗相关并发症： 如骨髓抑制（贫血、白细胞减少、血小板减少）、胃肠道反应（恶心、呕吐、腹泻）、脱发、周围神经病变等。需要统计这些并发症的发生率及分级。
  • 靶向治疗相关并发症： 如EGFR-TKI导致的皮疹、腹泻、肝功能异常等。
  • 外科手术相关并发症： 如肺漏气、出血、感染、肺栓塞等。对于接受手术的患者，需统计术后并发症发生率。例如，一项关于新辅助卡瑞利珠单抗治疗NSCLC的研究显示，21.9%的患者出现术后并发症，最常见的是咳嗽和疼痛 75。另一项研究发现，接受辅助化疗的NSCLC患者血栓栓塞事件（TEE）的发生率为3.3%，且无致死性TEE，提示该人群TEE风险低于既往报道的姑息性化疗患者 76。

通过对这些治疗相关并发症的详细统计和风险因素分析，本研究旨在为临床医生提供更全面的信息，以便在制定治疗方案时充分评估风险，并提前采取预防和管理措施，从而提高患者的治疗安全性和依从性。

5.2 合并症对预后的调节作用

非小细胞肺癌（NSCLC）患者往往伴随一种或多种合并症，这些合并症不仅影响患者的体力状况和治疗选择，还在复杂的作用机制下显著调节NSCLC的疾病进展和预后。通过对2000例电子病历数据的深入分析，本研究旨在评估高血压、糖尿病、慢性阻塞性肺疾病（COPD）等常见合并症对NSCLC患者治疗耐受性、治疗反应以及生存结局的具体影响，并探讨这些合并症如何通过炎症、代谢紊乱或器官功能受损等机制，调节NSCLC的整体预后。

1. 常见合并症对NSCLC预后的影响

合并症在肺癌患者中普遍存在，其发生率随年龄增长而增加 77。对合并症的评估通常采用Charlson合并症指数（CCI）等量化工具，CCI评分越高，预后通常越差 78。本研究将统计主要合并症（如心血管疾病、糖尿病、COPD、肝肾功能不全等）在队列中的发生率，并分析不同合并症数量和类型对患者总生存期（OS）和无进展生存期（PFS）的影响。

  • 慢性阻塞性肺疾病（COPD）： COPD是NSCLC最常见的合并症之一，且是肺癌发生的重要危险因素。COPD患者的肺功能往往较差，这限制了他们接受手术切除和同步放化疗的潜力 79。此外，COPD引起的慢性炎症环境可能促进肿瘤进展。有研究表明，合并间质性肺异常（ILA）的NSCLC患者预后较差 80。本研究将分析合并COPD患者的治疗选择倾向（如是否更倾向于SBRT而非手术），以及其对治疗耐受性（如放射性肺炎发生率）和生存结局的影响。
  • 糖尿病（Diabetes Mellitus, DM）： 糖尿病作为一种常见的代谢性疾病，对肿瘤的发生发展和治疗预后均有影响。一项针对NSCLC患者的Meta分析显示，糖尿病是NSCLC术后患者总生存期的独立不利预后因素 81。糖尿病可能通过高血糖、高胰岛素血症及慢性炎症等途径促进肿瘤细胞增殖、转移和耐药。本研究将探讨糖尿病对NSCLC患者治疗反应（如对靶向治疗或免疫治疗的敏感性）和生存结局的调节作用，并考虑糖尿病类型（I型或II型）、血糖控制情况以及是否使用特定降糖药物（如二甲双胍）的影响。
  • 高血压和心血管疾病： 高血压和冠心病等心血管合并症在老年NSCLC患者中非常普遍。这些疾病可能增加治疗相关并发症的风险，例如，对中心型肿瘤进行立体定向放疗（SBRT）可能导致过度毒性 82。心血管疾病患者可能需要调整抗肿瘤治疗方案，以避免不良事件。本研究将分析心血管合并症对治疗选择、治疗完成率以及生存结局的影响，并评估其是否与特定不良事件（如心血管事件）的发生率增加相关。
  • 间质性肺病（Interstitial Lung Disease, ILD）： 间质性肺病，特别是间质性肺异常（ILA），是NSCLC患者发生不良预后的显著因素 80。免疫检查点抑制剂相关的肺炎（CIP）也是一个值得关注的风险 68。这类患者的治疗选择可能受限，预后通常较差。本研究将统计合并ILD的NSCLC患者比例，并重点分析其治疗方案选择、并发症发生率和生存结局，以期为这类高危患者提供更优的治疗建议。
  • 其他合并症： 肝肾功能不全、感染、贫血等也可能影响NSCLC患者的治疗耐受性和预后。例如，贫血可能影响化疗剂量强度，肝肾功能不全则会限制药物选择和剂量。本研究将全面分析这些合并症对患者整体预后的调节作用。

2. 合并症对治疗耐受性和反应的影响机制

合并症对NSCLC治疗的影响是多方面的：

  • 对治疗方案选择的限制： 严重的合并症可能导致患者无法耐受标准治疗强度，例如，年龄较大的患者可能由于合并症而非手术适应症接受治疗 79。
  • 增加治疗相关并发症风险： 如上所述，间质性肺异常（ILA）患者发生不良预后的风险增加 80。
  • 影响药物代谢和毒性： 肝肾功能不全会影响药物的代谢和排泄，导致药物在体内蓄积，增加毒性反应。
  • 对肿瘤微环境的调节： 慢性炎症（如COPD引起的炎症）、代谢紊乱（如糖尿病引起的高血糖）可能改变肿瘤微环境，影响肿瘤的生长、转移和对治疗的敏感性。例如，系统性炎症水平较高（如ALI和IBI评分异常）的患者预后更差 8384。
  • 患者依从性： 复杂的合并症管理可能分散患者的精力，影响其对肿瘤治疗的依从性。

3. 合并症管理优化策略

基于对电子病历数据的分析结果，本研究将提出针对NSCLC患者合并症管理的优化策略：

  • 早期筛查与评估： 在诊断NSCLC时，应常规对患者的合并症进行全面筛查和评估，包括肺功能、心功能、血糖、肝肾功能等，并采用量化工具（如CCI）评估合并症的严重程度。
  • 个体化治疗方案制定： 根据患者的合并症情况，个体化调整NSCLC治疗方案。例如，对于伴有严重COPD的患者，可优先考虑SBRT；对于糖尿病患者，应在治疗过程中严密监测血糖，并可能调整降糖药物。
  • 多学科协作管理： 鼓励肿瘤科、呼吸科、心血管科、内分泌科等多学科专家共同参与患者的诊疗决策，对合并症进行积极管理和干预，以降低治疗风险，提高患者的耐受性。
  • 优化支持治疗： 针对合并症可能带来的不良反应，加强支持治疗，例如，对于COPD患者，提供充分的呼吸支持和康复指导；对于糖尿病患者，进行营养管理和血糖控制。
  • 患者教育： 加强对患者及其家属的健康教育，使其了解合并症对治疗和预后的影响，提高患者自我管理能力和治疗依从性。

通过对合并症的深入研究，本研究旨在为NSCLC患者提供更全面、更安全的诊疗方案，从而提高患者的整体生存质量和长期预后。

6.1 数据完整性与一致性评估

电子病历（EHR）数据为真实世界研究提供了宝贵资源，但其数据质量，特别是完整性和一致性，直接影响研究的可靠性和结论的有效性。对于2000例非小细胞肺癌（NSCLC）电子病历数据，对关键字段进行完整性与一致性评估是研究开展的前提。

1. 关键字段缺失率统计

全面评估电子病历中核心临床和病理信息的缺失情况至关重要。我们将重点关注以下关键字段：

  • 病理类型： NSCLC的准确病理分型（腺癌、鳞癌、大细胞癌等）是指导治疗和判断预后的基石。由于不同病理类型具有不同的分子特征和治疗敏感性，病理类型缺失或模糊（如仅记录“NSCLC未另行说明”）将严重影响后续分析的精准度。我们将统计病理类型明确记录的比例，以及模糊或缺失的比例。
  • 分子检测结果： 驱动基因突变（如EGFR、ALK、ROS1、BRAF、MET等）和PD-L1表达状态是晚期NSCLC靶向治疗和免疫治疗的关键依据。分子检测结果的缺失可能导致无法评估患者是否接受了精准治疗，或无法进行疗效的亚组分析。我们将统计EGFR、ALK、ROS1、PD-L1等各项分子检测的执行率，以及报告结果的完整性（例如，EGFR是记录为突变、野生型还是未检测）。已有研究指出，电子病历中吸烟史等数据的准确性可能存在不足，但多变量模型能更好地利用这些不准确数据进行预测 85。
  • TNM分期： 准确的TNM分期对于疾病诊断、预后评估和治疗决策至关重要。电子病历中可能存在分期信息不完整（如仅记录临床分期而无病理分期）、记录方式不统一（如使用不同版本的TNM分期标准）或信息缺失的情况。我们将评估I、II、III、IV期患者分期信息的完整性及具体T、N、M参数的缺失率。
  • 治疗方案： 详细的治疗方案（如手术方式、放疗剂量与次数、化疗方案、靶向药物名称及剂量、免疫治疗药物名称）对于疗效评估和治疗模式分析是必需的。我们将统计各类治疗方案记录的完整性和具体性。
  • 生存结局： 总生存期（OS）和无进展生存期（PFS）的准确计算依赖于患者的死亡日期、进展日期和末次随访日期。这些日期信息的缺失或不准确将直接影响生存分析的可靠性。
  • 吸烟史： 吸烟史作为肺癌的重要危险因素，其记录的详细程度（如吸烟包年数、戒烟时间）直接影响风险评估。电子病历中对吸烟暴露的记录可能不准确，但这并不妨碍使用模型进行风险评估 85。

2. 术语标准化程度分析

不同医疗机构或同一机构不同医生在记录电子病历时，可能存在术语使用、数据格式和记录习惯上的差异，导致数据一致性问题，这在临床研究中是常见的挑战。已有研究在妇产科电子病历中发现数据存在准确性和完整性方面的例外情况，这可能与软件的可用性有关 86。

  • 分期记录差异： 肺癌TNM分期标准自2009年第七版以来，已更新至第八版（2017年），并将于2024年发布第九版。不同版本的分期标准对T、N、M的定义有所调整，例如，第七版中的TNM分期与第八版中的分组规则存在差异。在电子病历数据中，可能同时存在按不同版本记录的分期信息。因此，需要识别并统一分期标准，或在分析中明确指出所使用的分期版本。
  • 病理诊断描述： 某些病理报告可能使用不同的描述词汇，例如，“非小细胞肺癌，无法进一步分类（NSCLC-NOS）”与明确的腺癌或鳞癌诊断。需要评估这些非标准化描述的比例，并尝试进行人工复核或利用自然语言处理（NLP）技术进行归一化处理。
  • 分子检测报告格式： 不同实验室的分子检测报告格式和结果表述可能不尽相同，例如，EGFR突变的类型、PD-L1表达的评估方法（如22C3、28-8抗体及相应的TPS阈值）。需要统一这些检测结果的呈现方式，以便进行有效的数据整合和比较。
  • 治疗方案细节： 化疗方案的名称、放疗方案的剂量分割方式、靶向药和免疫药的具体名称和给药频率，可能存在缩写或非标准名称，需要进行统一编码。

3. 数据完整性与一致性评估的方法

  • 描述性统计： 计算各关键字段的缺失率，直观呈现数据完整性。
  • 交叉验证/人工抽样核查： 对部分数据进行人工抽样核查，验证电子病历记录与原始病案资料的一致性，评估录入错误或转录误差的发生率。
  • 自然语言处理 (NLP) 技术： 对于非结构化文本数据（如病理报告、放射报告中的描述），可以利用NLP技术进行信息提取和标准化，以弥补结构化数据的不足。例如，有研究表明NLP能有效从电子病历中提取晚期肺癌患者的临床数据，且效率高、外在效度良好 87。然而，也有研究指出，基于RECIST标准从EHR中提取肿瘤进展信息存在挑战，放射学报告的清晰度和完整性不足 88。因此，需要权衡NLP的优势与局限性。
  • 数据清洗与转换： 对不一致的术语和格式进行清洗和转换，使其符合统一标准，便于后续的统计分析。
  • 隐私保护记录链接： 在多中心数据整合时，需要采用隐私保护技术对去识别化的患者记录进行准确链接，以提高数据完整性和横向一致性 89。

通过上述评估，将清晰地界定本研究数据的基础质量，并为后续的数据预处理和分析提供指导，确保研究结果的稳健性。

6.2 真实世界研究的偏倚控制

真实世界数据（Real-World Data, RWD）来源于日常临床实践，具有样本量大、覆盖范围广等优势，为临床研究提供了宝贵的机会。然而，与严格控制的随机对照试验（Randomized Controlled Trial, RCT）不同，电子病历数据作为一种重要的RWD来源，其非随机性决定了真实世界研究必然面临各种偏倚的挑战。在利用2000例非小细胞肺癌（NSCLC）电子病历数据进行研究时，识别并有效控制这些偏倚是确保研究结论科学性和可靠性的关键。

1. 选择偏倚 (Selection Bias)

选择偏倚是指研究对象的选择或从研究中退出不是随机的，导致样本不能代表目标人群，从而影响研究结果的外推性。

  • 分子检测率差异导致的偏倚： 电子病历数据中，接受分子检测的患者往往是基于临床怀疑或特定治疗需求。例如，年轻、非吸烟的腺癌患者可能更容易接受EGFR突变检测。这种非随机检测可能导致样本中特定基因突变阳性率与真实世界发病率存在偏差。此外，由于“延迟入组”（delayed entry）现象，只有在基因检测结果可用后才被纳入分析的患者可能本身就是长期生存者，这可能导致生存分析结果高估。有研究指出，临床基因组数据库（clinico-genomic databases）倾向于纳入长期生存者，从而导致OS分析结果可能存在偏倚，并建议在分析时评估“独立延迟入组”假设是否满足 90。为了应对这种偏倚，可以采用敏感性分析来评估未检测患者对结果的影响，或者通过更复杂的统计方法（如多重插补）来处理缺失数据。
  • 健康患者效应： 那些体力状况较好、合并症较少、能够耐受积极治疗的患者，其数据更容易被完整记录在电子病历中，并且更可能接受最新、最有效的治疗方案。这可能导致研究结果倾向于显示更优的治疗效果或预后，而忽略了那些体力状况较差、无法接受积极治疗的患者群体。
  • 数据可用性偏倚： 只有数据完整且可用的患者才会被纳入最终分析，而那些数据缺失较多的患者可能被排除。研究显示，国家癌症数据库（National Cancer Database）中，高达71%的NSCLC患者存在感兴趣变量的缺失数据，且这些缺失数据的患者2年OS显著低于数据完整的患者（33.2% vs 51.6%），这表明缺失数据并非随机分布，而是与患者预后相关 91。为了降低这种偏倚，应尽可能减少因数据缺失而剔除患者，并采用恰当的缺失数据处理方法。

2. 信息偏倚 (Information Bias)

信息偏倚是指研究中测量或记录的数据存在系统性误差，导致暴露、结局或混杂因素的分类不准确。

  • 结局事件（如死亡）记录不完整： 电子病历数据中，死亡信息可能存在不完整或延迟记录的情况。如果死亡事件未被完全捕获，可能导致总生存期（OS）被高估 92。一项研究评估了Flatiron Health肿瘤数据库中死亡数据缺失对NSCLC患者OS分析的影响，结果显示，即使在91%敏感度的情况下，OS中位数仍有0.6-0.9个月的偏差，而在较低敏感度模拟下，偏差可达3.3-9.7个月 93。为解决此问题，可以尝试将电子病历数据与外部死亡登记数据（如社会保障死亡指数或国家死亡指数NDI）进行链接，以提高死亡事件记录的完整性和准确性 92。
  • 症状记录及时性与准确性： 电子病历中症状的记录可能依赖于患者的主诉和医生的记录习惯，存在主观性和滞后性。例如，疾病进展的记录可能因影像学检查频率的差异而产生偏差。研究表明，在真实世界中，不同治疗类型患者的影像学评估频率可能不同，这可能导致PFS等结局评估产生偏倚，尤其是在疾病进展时间非常短的情况下 94。

3. 混杂偏倚 (Confounding Bias)

混杂偏倚是指一个与暴露和结局均相关的因素，但并非暴露和结局之间的中间环节，从而扭曲了暴露与结局之间真实关联的强度或方向。在真实世界研究中，由于患者接受治疗并非随机分配，混杂偏倚尤为突出。

  • 治疗选择的混杂： 患者接受何种治疗通常是基于其疾病分期、体力状况、合并症、分子标志物状态以及医生的临床判断等多种因素。例如，体力状况较好的患者可能更倾向于接受激进治疗（如手术或联合免疫化疗），而体力状况较差的患者则选择姑息治疗。这种基于预后因素的治疗选择差异会造成“治疗适应症混杂”（confounding by indication），使得表面上某种治疗效果更好，但实际上是由于接受该治疗的患者本身预后较好 95。
  • 未测量混杂： 电子病历中可能缺乏某些重要的临床或预后信息（如患者依从性、社会经济状况、详细的基因组学数据），这些“未测量混杂因素”无法在统计分析中进行调整，从而导致残余混杂偏倚 95。

应对策略：

为控制上述偏倚，提高研究结果的可靠性，可以采取以下策略：

  • 研究设计阶段：
    • 严格的入排标准： 明确定义研究人群，尽量排除数据质量差或信息不完整的患者。
    • 考虑外部对照组： 在单臂试验或缺乏对照组的情况下，可以尝试构建外部对照组（External Control Arm, ECA）。但需要注意的是，ECA的使用需要高度关注选择偏倚和未测量混杂，并应用定量偏倚分析（Quantitative Bias Analysis, QBA）来评估结果的稳健性 969798。
  • 数据分析阶段：
    • 多变量调整： 采用Cox比例风险模型、逻辑回归等统计模型，将已知且可测量的混杂因素纳入模型进行调整。
    • 倾向得分方法 (Propensity Score Methods)： 包括倾向得分匹配（PSM）、倾向得分加权（Inverse Probability of Treatment Weighting, IPTW）等，通过平衡不同治疗组间的基线特征，模拟随机化过程，有效控制混杂偏倚 99。
    • 敏感性分析 (Sensitivity Analysis)： 评估在不同假设（如数据缺失模式、未测量混杂强度）下，研究结果的稳健性。例如，可以假设缺失数据是非随机缺失，或假设存在未测量混杂因素并量化其对结果的影响，以评估研究结论的可靠程度 9799。
    • 定量偏倚分析 (Quantitative Bias Analysis, QBA)： QBA是一系列用于量化系统误差（无法通过常规统计调整解决）的技术，例如评估未测量混杂、测量误差和选择偏倚对结果的影响。这对于评估真实世界数据与临床试验数据比较的有效性尤为重要 9798。
    • 分层分析和亚组分析： 根据关键混杂因素（如疾病分期、ECOG评分、分子标志物状态）进行分层或亚组分析，以观察不同亚组中的治疗效果是否一致，从而揭示潜在的异质性。
    • 时间依赖性混杂处理： 对于随时间变化的混杂因素（如患者体力状况、肿瘤负荷），需要采用更高级的统计方法，如边缘结构模型（Marginal Structural Models）或G-估计（G-estimation），以正确估计治疗效果。
    • 数据验证与清洗： 对电子病历数据进行严格的质量控制，识别和纠正数据录入错误、逻辑冲突等问题。对于重要的缺失数据，可尝试通过人工复核病历或多重插补等方法进行补充。

通过系统地考虑和应对这些偏倚，本研究将最大限度地从2000例非小细胞肺癌电子病历数据中提取出高质量的真实世界证据，为临床决策提供更有价值的参考。

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Xinan Wang, Christopher W Romero-Gutierrez, Jui Kothari, et al.
JAMA Netw Open. 2023 May 1;6(5):e2311966. doi: 10.1001/jamanetworkopen.2023.11966.
IMPORTANCE: Lung cancer remains the leading cause of cancer-related death globally; non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, and cigarette smoking is the factor most significantly associated with its risk. However, little is known about the association of years since prediagnosis smoking cessation and cumulative smoking with overall survival (OS) following a lung cancer diagnosis. OBJECTIVE: To characterize the association of years since smoking cessation before diagnosis and cumulative smoking pack-years with OS in patients with NSCLC in a lung cancer survivor cohort. DESIGN, SETTING, AND PARTICIPANTS: The cohort study involved patients with NSCLC who were recruited to the Boston Lung Cancer Survival Cohort at Massachusetts General Hospital (Boston, Massachusetts) between 1992 and 2022. Patients' smoking history and baseline clinicopathological characteristics were prospectively collected through questionnaires, and OS following lung cancer diagnosis was regularly updated. EXPOSURES: Duration of smoking cessation before a lung cancer diagnosis. MAIN OUTCOMES AND MEASURES: The primary outcome was the association of detailed smoking history with OS following a lung cancer diagnosis. RESULTS: Of 5594 patients with NSCLC (mean [SD] age, 65.6 [10.8] years; 2987 men [53.4%]), 795 (14.2%) were never smokers, 3308 (59.1%) were former smokers, and 1491 (26.7%) were current smokers. Cox regression analysis suggested that former smokers had 26% higher mortality (hazard ratio [HR], 1.26; 95% CI, 1.13-1.40; P < .001) and current smokers had 68% higher mortality (HR, 1.68; 95% CI, 1.50-1.89; P < .001) compared with never smokers. Log2-transformed years since smoking cessation before diagnosis were associated with significantly lower mortality among ever smokers (HR, 0.96; 95% CI, 0.93-0.99; P = .003). Subgroup analysis, stratified by clinical stage at diagnosis, revealed that former and current smokers had even shorter OS among patients with early-stage disease. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with NSCLC, quitting smoking early was associated with lower mortality following a lung cancer diagnosis, and the association of smoking history with OS may have varied depending on clinical stage at diagnosis, potentially owing to the differing treatment regimens and efficacy associated with smoking exposure following diagnosis. Detailed smoking history collection should be incorporated into future epidemiological and clinical studies to improve lung cancer prognosis and treatment selection.

6Immunotherapy in advanced Non-Small Cell Lung Cancer patients with poor performance status: The role of clinical-pathological variables and inflammatory biomarkers.PubMed

Riccardo Lobefaro, Giuseppe Viscardi, Raimondo Di Liello, et al.
Lung Cancer. 2021 Feb;152:165-173. doi: 10.1016/j.lungcan.2020.12.027. Epub 2020 Dec 28.
BACKGROUND: The introduction of immunotherapy has improved the prognosis of patients with Non-Small Cell Lung Cancer (NSCLC). However, data in poor ECOG Performance Status (PS) patients remain scant due to their exclusion from randomized trials. MATERIAL AND METHODS: We analyzed data of patients with advanced NSCLC treated with immunotherapy in two Italian Centers, to evaluate the impact of PS (0-1 vs 2) on disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Chi-square test was used to compare clinical-pathological variables, their impact on survival was evaluated through Cox proportional hazard models. RESULTS: Among 404 patients included, PS was 0 in 137 (33.9 %), 1 in 208 (51.5 %) and 2 in 59 (14.6 %) patients; 143 were female and 90 had squamous NSCLC. Clinical-pathological variables were uniformly distributed except for higher prevalence of liver metastases in patients with poor PS. We found that PS2 patients showed worse outcomes in terms of DCR (21.8 % vs 50.3 %, p = 0.001), PFS [2.0 (95 % CI 1.6-3.0) vs 3.0 (95 % CI 2.7-4.0) months, p < 0.0001] and OS [4.0 (95 % CI 2.8-5.7) vs 13.2 (95 % CI 11.0-15.8) months, p < 0.0001]. PS2 status, negative PDL1 expression and early corticosteroids exposure as well as higher Neutrophil to Lymphocyte Ratio and LDH at baseline were associated with worse outcomes at univariate and multivariable analysis. Subgroup analysis confirmed poor outcomes in PS2 patients with high LDH and concomitant corticosteroid therapies. The incidence of Grade 3/4 adverse events was 11.3 % in PS 0-1 and 10.2 % in PS 2 patients (p = 0.81). CONCLUSION: Our data confirm reduced efficacy of immunotherapy in patients with poor PS even though a good safety. Despite PS remains the most powerful independent prognostic factor for NSCLC, LDH levels and steroids exposure could support the decision making in PS2 patients.

7Trends in treatment of non-small cell lung cancer in Finland 2014-2019.PubMed

Riikka-Leena Leskelä, Emmi Peltonen, Ira Haavisto, et al.
Acta Oncol. 2022 May;61(5):641-648. doi: 10.1080/0284186X.2022.2042474. Epub 2022 Apr 12.
INTRODUCTION: Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality in the Western world. However, emerging treatment options and more patients directed to active treatments might improve the outcomes. Here, we retrospectively studied the patient characteristics and treatment practices for NSCLC in Finland 2014-2019 with a special focus on changes in trends over time. MATERIAL AND METHODS: The cohort consisted of patients diagnosed with NSCLC in Finland 2014-2018. Cancer treatments for the patients were followed until the end of 2019. The data, both structured and unstructured, were collected from electronic medical records of four university hospitals in Finland. RESULTS: Of the study population ( = 4047), 65% had adenocarcinoma and 29% squamous cell carcinoma. The share of patients who had not received any active treatment (except palliative radiotherapy) decreased from 32% to 18% between 2014-18. The percentage of patients receiving surgery increased slightly from 22.7% to 24% and for patients receiving chemotherapy or immuno-oncological (IO) treatments from 29% to 41.2% and from 0.8% to 8%, respectively between, 2014-18. However, the time of treatment for patients receiving systemic cancer treatments did not change during the same time period. DISCUSSION: The current study suggests a trend in NSCLC towards more active treatment approaches in 2014-18.

8MET Exon 14 Skipping in NSCLC: A Systematic Literature Review of Epidemiology, Clinical Characteristics, and Outcomes.PubMed

Julien Mazieres, Helene Vioix, Boris M Pfeiffer, et al.
Clin Lung Cancer. 2023 Sep;24(6):483-497. doi: 10.1016/j.cllc.2023.06.008. Epub 2023 Jun 18.
INTRODUCTION: MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes. METHODS: On June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC. RESULTS: We included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy. CONCLUSIONS: Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.

9Presence of a 34-gene signature is a favorable prognostic marker in squamous non-small cell lung carcinoma.PubMed

W S M E Theelen, O Krijgsman, K Monkhorst, et al.
J Transl Med. 2020 Jul 3;18(1):271. doi: 10.1186/s12967-020-02436-3.
BACKGROUND: The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC). METHODS: Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system. RESULTS: Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology. CONCLUSIONS: These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures.

10Treatment, no treatment and early death in Danish stage I lung cancer patients.PubMed

Niels Lyhne Christensen, Susanne Dalton, Jesper Ravn, et al.
Lung Cancer. 2019 May;131:1-5. doi: 10.1016/j.lungcan.2019.03.007. Epub 2019 Mar 9.
BACKGROUND: Stage I lung cancer is curable with surgery as the treatment of choice. Other effective and curative treatments exist. Nevertheless, some patients only receive palliative treatment and some receive no treatment at all. MATERIALS AND METHODS: Using the Danish Lung Cancer Registry (DLCR), we assessed treatment distribution for a population-based Danish cohort of stage I lung cancer patients diagnosed from 2011 to 2014. We assessed one-year mortality according to treatment. Furthermore, in a nested case-control study based on data from medical records, we assessed the reason for not undergoing treatment among patients in favourable performance status (PS) with no treatment registration in the DLCR. RESULTS: We identified 2985 patients, 68% (n = 2021) were treated surgically and 17% (n = 508) were managed with curative oncological therapy. The unadjusted odds ratio (OR) for death within one year was 2.5 (95% CI, 1.8-3.3) for the oncologically managed vs. the surgically treated. After adjusting for age, lung function and PS, the OR was 1.2 (95% CI, 0.8-1.9). Among 129 patients with a PS of 0-1 and no treatment registration, we established the reason for not undergoing treatment in 122 (95%). The majority (70%) were misclassified and did either not have lung cancer, had more advanced disease or were curatively treated. The 36 (30%) patients that did not undergo treatment, had a lower prevalence of adenocarcinomas (17 vs. 51%, p = 0.003), more comorbidites (median Charlson comorbidity index score 2 vs. 1, p < 0.001) and high alcohol intake (19 vs. 7%, p = 0.04) as compared to surgically treated controls. The primary reasons for no treatment were; comorbidity, patient decision and disease progression. CONCLUSION: Difference in outcome between the two major treatment groups was confounded by age, lung function and PS. Comorbidity, high alcohol intake and histology were associated with not undergoing curative treatment in spite of a favourable PS.

11Lung cancer survival trends and prognostic factors: A 26-year population-based study in Girona Province, Spain.PubMed

Eduard Teixidor-Vilà, Jan Trallero, Montse Puigdemont, et al.
Lung Cancer. 2024 Nov;197:107995. doi: 10.1016/j.lungcan.2024.107995. Epub 2024 Oct 20.
BACKGROUND: Lung cancer (LC) is Europe's primary cause of cancer-related mortality largely due to its historically low survival rates. The aim of this study was to analyze 26-year survival trends in the province of Girona, Spain, and to identify key prognostic factors. METHODS: Population-based study of LC cases collected between 1994 and 2019, with follow-up until December 31, 2021. Variables included date of diagnosis, sex, age, histology, and tumor stage (the latter since 2010). Diagnosis dates were categorized into three periods (1994-2002, 2003-2011, and 2012-2019). Multivariate flexible parametric models, incorporating age as a non-linear, time-varying covariate, were used to analyze net survival (NS) and trends. Annual absolute change in survival (AAC_S) was calculated using 3-year NS. RESULTS: The analysis of 9,113 LC cases showed a NS improvement between the first and last period (7.1 months (95 %CI: 6.5;7.6) to 8.5 months (95 %CI: 7.9;9.1)). Squamous cell carcinoma (NSC-SCC) showed the greatest improvement with an AAC_S of 0.32 % (95 % CI: 0.21; 0.43), while survival for non-small cell lung cancer not otherwise specified declined (AAC_S of -0.19 % (95 %CI: -0.26; -0.12)). Prognostic analysis of the 3,642 cases (2010-2019) indicated a lower LC death risk for adenocarcinoma and NSC-SCC compared to LC not otherwise specified (HR 0.52 and 0.62, respectively). Increasing tumor stage correlated with higher LC mortality risk (1.8-, 4.0-, and 10.1-fold increase for stage II, III, and IV, respectively, compared to stage I). CONCLUSIONS: LC survival has notably improved, particularly for NSC-SCC. Survival is influenced by sex, age, date of diagnosis, tumor histology and especially by stage, underscoring comprehensive data collection's importance.

12Lung cancer: diagnosis and management.PubMed

Lauren G Collins, Christopher Haines, Robert Perkel, et al.
Am Fam Physician. 2007 Jan 1;75(1):56-63.
Lung cancer is the leading cause of cancer-related death in the United States, with an average five-year survival rate of 15 percent. Smoking remains the predominant risk factor for lung cancer. Lung cancers are categorized as small cell carcinoma or non-small cell carcinoma (e.g., adenocarcinoma, squamous cell carcinoma, large cell carcinoma). These categories are used for treatment decisions and determining prognosis. Signs and symptoms may vary depending on tumor type and extent of metastases. The diagnostic evaluation of patients with suspected lung cancer includes tissue diagnosis; a complete staging work-up, including evaluation of metastases; and a functional patient evaluation. Histologic diagnosis may be obtained with sputum cytology, thoracentesis, accessible lymph node biopsy, bronchoscopy, transthoracic needle aspiration, video-assisted thoracoscopy, or thoracotomy. Initial evaluation for metastatic disease relies on patient history and physical examination, laboratory tests, chest computed tomography, positron emission tomography, and tissue confirmation of mediastinal involvement. Further evaluation for metastases depends on the clinical presentation. Treatment and prognosis are closely tied to the type and stage of the tumor identified. For stages I through IIIA non-small cell carcinoma, surgical resection is preferred. Advanced non-small cell carcinoma is treated with a multimodality approach that may include radiotherapy, chemotherapy, and palliative care. Chemotherapy (combined with radiotherapy for limited disease) is the mainstay of treatment for small cell carcinoma. No major organization recommends screening for early detection of lung cancer, although screening has interested researchers and physicians. Smoking cessation remains the critical component of preventive primary care.

13Description and Survival of Stage I and II Lung Cancer Patients.PubMed

Olaia Pérez-Martínez, Iria Vidal-García, Carmen Montero-Martínez, et al.
Arch Bronconeumol (Engl Ed). 2018 Aug;54(8):420-426. doi: 10.1016/j.arbres.2018.02.007. Epub 2018 Mar 16.
INTRODUCTION: The objective of our study was to describe the characteristics of patients diagnosed with stage I and II lung cancer in the health area of A Coruña (Galicia) and to determine their overall survival according to certain variables. METHODS: Retrospective case series in patients diagnosed between January 2011 and December 2015 with stage I and II primary lung cancer with a minimum follow-up of 18 months. RESULTS: 158 patients were included, 99 at stage I, with a median age of 69 years [range 20-90], predominantly men (81%). Adenocarcinoma was the most common histology (52.9%), followed by epidermoid carcinoma (33.1%). Asymptomatic patients (35.9%) presented more frequently in stage I. Median survival was 57 months (95% CI 48.1-65.9), with higher survival among women, patients under 70 years of age, and those who received surgical treatment. CONCLUSIONS: Early stage lung cancer in the health area of A Coruña occurs predominantly in men, in advanced age, and with adenocarcinoma histology. Survival was greater among patients with stage I disease, women, individuals aged under 70 years, and those treated surgically. Despite early diagnosis, median survival was less than 5 years.

14Metastatic index of non-small-cell lung cancer and long-term survival.PubMed

Michael Poullis, Michael Shackcloth, Richard Page, et al.
Asian Cardiovasc Thorac Ann. 2015 Feb;23(2):185-90. doi: 10.1177/0218492314545833. Epub 2014 Aug 7.
AIM: We aimed to determine whether metastatic index is a factor determining long-term survival in patients undergoing curative resection for non-small-cell lung cancer. METHODS: There were 2695 consecutive pulmonary resections performed between October 2001 and September 2011 in our institution; 1795 were potentially curative resections for non-small-cell lung cancer with bronchial margin length data available. Benchmarking against the International Association for the Study of Lung Cancer data set was performed. Cox multivariate analysis was undertaken. Metastatic index was defined as N stage× bronchial resection margin length. RESULTS: Benchmarking failed to reveal any significant differences between our data and the International Association for the Study of Lung Cancer data set. Univariate analysis identified metastatic index as a significant factor determining long-term survival (p = 0.04). Cox regression demonstrated that metastatic index (hazard ratio 1.29, p = 0.0002), age (hazard ratio 1.02, p < 0.0001), body mass index (hazard ratio 0.98, p = 0.006), female sex (hazard ratio 0.65, p < 0.0001), T1 stage (hazard ratio 0.67, p < 0.0001), T2 stage (hazard ratio 2.13, p < 0.0001), T3 stage (hazard ratio 1.59, p = 0.03), forced expiratory volume in 1 s (hazard ratio 0.70, p < 0.0001), pneumonectomy (hazard ratio 1.43, p = 0.001), histology subtype adenosquamous (hazard ratio 3.77, p = 0.01) and squamous (hazard ratio 0.83, p = 0.03) were all significant determinants of long-term survival. CONCLUSION: Metastatic index is a significant factor determining long-term survival in patents with adenocarcinoma undergoing potentially curative surgery with a lobectomy.

15Association between event-free survival and overall survival after neoadjuvant treatment for non-small cell lung cancer: a systematic review and meta-analysis.PubMed

Gyula Ostoros, Robert Hettle, Nefeli Georgoulia, et al.
Expert Rev Anticancer Ther. 2023 Jul-Dec;23(12):1305-1313. doi: 10.1080/14737140.2023.2272645. Epub 2023 Dec 8.
BACKGROUND: We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. RESEARCH DESIGN AND METHODS: Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I-IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. RESULTS: We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient = 0.864; 95% confidence interval 0.809-0.992; = 0.006; random-effects meta-regression, R = 0.777). CONCLUSIONS: We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC.

16Practical Management of Oligometastatic Non-Small-Cell Lung Cancer.PubMed

Katie Jasper, Brendon Stiles, Fiona McDonald, et al.
J Clin Oncol. 2022 Feb 20;40(6):635-641. doi: 10.1200/JCO.21.01719. Epub 2022 Jan 5.
Local ablative therapies, including surgery or stereotactic radiotherapy (SABR), are becoming an integral component in the treatment of oligometastatic disease in non-small-cell lung cancer. In this review, we summarize recent randomized evidence supporting progression-free survival and overall survival benefits of local ablation in these patients, as well as upcoming phase III data which should help us better understand the ideal treatment conditions and provide more insight into the oligometastatic state. Since practical management of oligometastatic disease in non-small-cell lung cancer can be challenging, we discuss a modern framework to identify patient, tumor, and treatment characteristics that can best guide management.

17Inoperable early stage non-small cell lung cancer: comorbidity, patterns of care and survival.PubMed

S L Smith, D Palma, T Parhar, et al.
Lung Cancer. 2011 Apr;72(1):39-44. doi: 10.1016/j.lungcan.2010.07.015.
PURPOSE: To evaluate comorbidities, patterns of care and outcomes for patients with inoperable stage I and II non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients diagnosed with stage I or II NSCLC in British Columbia between 1996 and 2005 who did not undergo primary surgery and were referred for oncology assessment were identified in a retrospective analysis. Baseline comorbidity and pulmonary function data for patients treated with curative radiotherapy (CurRT; biologically effective dose [BED]>58 Gy(10)) were abstracted by chart review. Kaplan-Meier and Cox regression were used to determine factors associated with overall survival (OS) and cause-specific survival (CSS) based on treatment group [no radiotherapy (NoRT), palliative radiotherapy (PallRT), or CurRT]. RESULTS: Of 1043 patients identified, approximately 1/3 received CurRT, and these patients had better performance status and lower stage disease than the other groups. There was a high prevalence of comorbid conditions in the CurRT group; 90% of CurRT patients had an age-adjusted Charlson comorbidity index (CCI) score ≥5. CurRT patients had a median survival 1-year longer than patients treated with PallRT or NoRT (p < 0.0001). In CurRT patients, CCI was predictive of OS (HR 1.1 per point CCI increase; p = 0.044), but not CSS. Patients receiving PallRT with a BED > 50 Gy(10) had significantly longer OS than those receiving PallRT of ≤50 Gy(10) (p < 0.0001). CONCLUSIONS: Treatment of medically inoperable early stage NSCLC patients with CurRT is associated with a significantly longer survival, and for these patients CCI is a significant predictor of OS. For patients treated with PallRT, higher doses of palliative thoracic RT is associated with improved OS.

18Sex and survival in non-small cell lung cancer: A nationwide cohort study.PubMed

Cecilia Radkiewicz, Paul William Dickman, Anna Louise Viktoria Johansson, et al.
PLoS One. 2019 Jun 27;14(6):e0219206. doi: 10.1371/journal.pone.0219206. eCollection 2019.
AIM: To in detail delineate sex differences in non-small cell lung cancer outcome and investigate possible underlying drivers. METHODS: We performed a nationwide, population-based cohort study using data on all incident cases of lung squamous cell carcinoma (n = 10,325) and adenocarcinoma (n = 23,465) recorded in the Swedish Lung Cancer Register in 2002-2016. Flexible parametric models were applied to compute adjusted female-to-male hazard ratios (aHRs) and standardized survival proportions over follow-up including age, calendar year, education, marital status, birth country, health care region, performance status, smoking history, comorbidities, and tumor location in the final model. RESULTS: Women presented with better performance status, were younger, and more often never-smokers. Women with adenocarcinoma also had lower comorbidity burden, less advanced stage, and were more often EGFR positive. Men with adenocarcinoma had a consistently poorer lung cancer-specific survival across stage; HR 0.69; 95% CI 0.63-0.76 (stage IA-IIB) to 0.94; 95% CI 0.88-0.99 (stage IIIB-IV), remaining largely unchanged after adjustments; aHR 0.74; 95% CI 0.66-0.82 to 0.84; 95% CI 0.81-0.87. The same pattern was observed in squamous cell carcinoma, except in stage IIIA disease, where we found no sex differences in survival. CONCLUSIONS: Men with non-small cell lung cancer have a consistently poorer prognosis, even after careful adjustments for a wide range of prognostic factors. While the pattern was similar in both squamous cell and adenocarcinoma, it was larger and more consistent in the latter.

19Abandoning the Notion of Non-Small Cell Lung Cancer.PubMed

Valeria Relli, Marco Trerotola, Emanuela Guerra, et al.
Trends Mol Med. 2019 Jul;25(7):585-594. doi: 10.1016/j.molmed.2019.04.012. Epub 2019 May 30.
Non-small cell lung cancers (NSCLCs) represent 85% of lung tumors. NSCLCs encompass multiple cancer types, such as adenocarcinomas (LUADs), squamous cell cancers (LUSCs), and large cell cancers. Among them, LUADs and LUSCs are the largest NSCLC subgroups. LUADs and LUSCs appear sharply distinct at the transcriptomic level, as well as for cellular control networks. LUADs show distinct genetic drivers and divergent prognostic profiles versus LUSCs. Therapeutic clinical trials in NSCLC indicate differential LUAD versus LUSC response to treatments. Hence, LUAD and LUSC appear to be vastly distinct diseases at the molecular, pathological, and clinical level. Abandoning the notion of NSCLC may critically help in developing novel, more effective subtype-specific molecular alteration-targeted therapeutic procedures.

20Location of stage I-III non-small cell lung cancer and survival rate: Systematic review and meta-analysis.PubMed

Hyun Woo Lee, Chang-Hoon Lee, Young Sik Park
Thorac Cancer. 2018 Dec;9(12):1614-1622. doi: 10.1111/1759-7714.12869. Epub 2018 Sep 27.
BACKGROUND: The association between the location of non-small cell lung cancer (NSCLC) and prognosis is a debated issue. Some studies have provided evidence of better prognosis of upper lobe tumors than lower to middle lobe tumors, while other studies have reported contrasting conclusions. The aim of this study was to further assess this association through a systematic review and meta-analysis. METHODS: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched up to 27 January 2017. Patients pathologically diagnosed with stage I-III NSCLC with three or five-year survival data were included. The main meta-analysis compared differences in survival rates according to the primary tumor location using the Mantel-Haenszel method with a random effect model. Sensitivity analysis was conducted according to lymph node metastasis, tumor node metastasis stage, staging method, and treatment modality. RESULTS: Ten clinical studies and 35 570 patients were recruited. Patients with tumors in the upper lobes had a higher rate of five-year survival compared to those with tumors in non-upper lobes (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.15-1.49). Similarly, the three-year survival rate was high in patients with tumors in the upper lobes (OR 1.99, 95% CI 1.02-3.86) and low in those with lower lobe tumors (OR 0.31, 95% CI 0.12-0.77). CONCLUSIONS: Stage I-III NSCLC located in the upper lobes showed higher five-year survival rates compared to other tumor locations.

21Development and Validation of a Nomogram Prognostic Model for Patients With Advanced Non-Small-Cell Lung Cancer.PubMed

Tao Wang, Rong Lu, Sunny Lai, et al.
Cancer Inform. 2019 Apr 5;18:1176935119837547. doi: 10.1177/1176935119837547. eCollection 2019.
IMPORTANCE: Nomogram prognostic models can facilitate cancer patient treatment plans and patient enrollment in clinical trials. OBJECTIVE: The primary objective is to provide an updated and accurate prognostic model for predicting the survival of advanced non-small-cell lung cancer (NSCLC) patients, and the secondary objective is to validate a published nomogram prognostic model for NSCLC using an independent patient cohort. DESIGN: 1817 patients with advanced NSCLC from the control arms of 4 Phase III randomized clinical trials were included in this study. Data from 524 NSCLC patients from one of these trials were used to validate a previously published nomogram and then used to develop an updated nomogram. Patients from the other 3 trials were used as independent validation cohorts of the new nomogram. The prognostic performances were comprehensively evaluated using hazard ratios, integrated area under the curve (AUC), concordance index, and calibration plots. SETTING: General community. MAIN OUTCOME: A nomogram model was developed to predict overall survival in NSCLC patients. RESULTS: We demonstrated the prognostic power of the previously published model in an independent cohort. The updated prognostic model contains the following variables: sex, histology, performance status, liver metastasis, hemoglobin level, white blood cell counts, peritoneal metastasis, skin metastasis, and lymphocyte percentage. This model was validated using various evaluation criteria on the 3 independent cohorts with heterogeneous NSCLC populations. In the SUN1087 patient cohort, the continuous risk score output by the nomogram achieved an integrated area under the receiver operating characteristics (ROC) curve of 0.83, a log-rank -value of 3.87e-11, and a concordance index of 0.717. In the SAVEONCO patient cohort, the integrated area under the ROC curve was 0.755, the log-rank -value was 4.94e-6 and the concordance index was 0.678. In the VITAL patient cohort, the integrated area under the ROC curve was 0.723, the log-rank -value was 1.36e-11, and the concordance index was 0.654. We implemented the proposed nomogram and several previously published prognostic models on an online Web server for easy user access. CONCLUSIONS: This nomogram model based on basic clinical features and routine lab testing predicts individual survival probabilities for advanced NSCLC and exhibits cross-study robustness.

22Molecular gene signature and prognosis of non-small cell lung cancer.PubMed

Poyin Huang, Chiou-Ling Cheng, Ya-Hsuan Chang, et al.
Oncotarget. 2016 Aug 9;7(32):51898-51907. doi: 10.18632/oncotarget.10622.
The current staging system for non-small cell lung cancer (NSCLC) is inadequate for predicting outcome. Risk score, a linear combination of the values for the expression of each gene multiplied by a weighting value which was estimated from univariate Cox proportional hazard regression, can be useful. The aim of this study is to analyze survival-related genes with TaqMan Low-Density Array (TLDA) and risk score to explore gene-signature in lung cancer. A total of 96 NSCLC specimens were collected and randomly assigned to a training (n = 48) or a testing cohort (n = 48). A panel of 219 survival-associated genes from published studies were used to develop a 6-gene risk score. The risk score was used to classify patients into high or low-risk signature and survival analysis was performed. Cox models were used to evaluate independent prognostic factors. A 6-gene signature including ABCC4, ADRBK2, KLHL23, PDS5A, UHRF1 and ZNF551 was identified. The risk score in both training (HR = 3.14, 95% CI: 1.14-8.67, p = 0.03) and testing cohorts (HR = 5.42, 95% CI: 1.56-18.84, p = 0.01) was the independent prognostic factor. In merged public datasets including GSE50081, GSE30219, GSE31210, GSE19188, GSE37745, GSE3141 and GSE31908, the risk score (HR = 1.50, 95% CI: 1.25-1.80, p < 0.0001) was also the independent prognostic factor. The risk score generated from expression of a small number of genes did perform well in predicting overall survival and may be useful in routine clinical practice.

23Development and Validation of a Nomogram for Predicting the 1-, 3-, and 5-year Survival in Patients with Acinar-predominant Lung Adenocarcinoma.PubMed

Zhi-Chao Zuo, Li-de Wang, Ke Peng, et al.
Curr Med Sci. 2022 Dec;42(6):1178-1185. doi: 10.1007/s11596-022-2672-7. Epub 2022 Dec 21.
OBJECTIVE: This study aimed to develop a nomogram to predict the overall survival (OS) of patients with acinar-predominant adenocarcinoma (APA). METHODS: Data from patients with APA obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2008 and 2016 were used. Significant prognostic factors were incorporated to construct a nomogram for predicting the 1-, 3-, and 5-year OS in these patients. The discrimination and calibration abilities of the nomogram were assessed using a C-index and calibration curves, respectively. RESULTS: A total of 2242 patients with APA were randomly divided into a training cohort (n=1576) and validation cohort (n=666). The independent prognostic factors for OS incorporated into the nomogram included marital status, age, gender, differentiation grade, T stage, N stage, and M stage. The nomogram showed good prediction capability, as indicated by the C-index [0.713, 95% confidence interval (CI): 0.705-0.721 in the training cohort, and 0.662, 95% CI: 0.649-0.775 in the validation cohort]. The calibration curves demonstrated that the 1-, 3-, and 5-year OS probabilities were consistent between the observed and predicted outcome frequencies. Patients were divided into the high-risk and low-risk groups with the former showing significantly worse survival than the latter (P<0.001). CONCLUSION: Using the SEER database, a nomogram was established to predict the 1-, 3-, and 5-year OS of patients with APA and was superior to the tumor size, lymph node, and metastasis staging system in terms of evaluating long-term prognosis.

24Development and validation of a radiomics-based nomogram for predicting a major pathological response to neoadjuvant immunochemotherapy for patients with potentially resectable non-small cell lung cancer.PubMed

Chaoyuan Liu, Wei Zhao, Junpeng Xie, et al.
Front Immunol. 2023 Feb 16;14:1115291. doi: 10.3389/fimmu.2023.1115291. eCollection 2023.
INTRODUCTION: The treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics. METHODS: A total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis. RESULTS: The radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable. DISCUSSION: The constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC.

25Development and validation a model for predicting overall survival of bladder cancer with lung metastasis: a population-based study.PubMed

Liang Liu, Fu-Zhen Sun, Pan-Ying Zhang, et al.
Eur J Med Res. 2023 Aug 10;28(1):279. doi: 10.1186/s40001-023-01261-w.
BACKGROUND: Although the number of patients with bladder cancer and lung metastasis is increasing there is no accurate model for predicting survival in these patients. METHODS: Patients enrolled in the Surveillance, Epidemiology, and End Results database between 2010 and 2015 were selected for the study. Univariate and multivariate Cox regression were used to determine independent prognostic factors, followed by development of a nomogram based on the multivariate Cox regression models. The consistency index, receiver operating characteristic curve, and calibration curve were used to validate the prognostic nomogram. RESULTS: 506 eligible bladder cancer patients with lung metastasis were enrolled in the study and then divided randomly into training and validation sets (n = 356 vs. n = 150). Multivariate Cox regression analysis indicated that age at diagnosis, primary site, histological type, surgery of the primary site, chemotherapy, bone metastasis, and liver metastasis were prognostic factors for overall survival (OS) in patients with lung metastasis in the training set. The C-index of the nomogram OS was 0.699 and 0.747 in the training and validation sets, respectively. ROC curve estimation of the nomogram in the training and validation sets showed acceptable accuracy for classifying 1-year survival, with an area under the curve (AUC) of 0.766 and 0.717, respectively. More importantly, the calibration plot showed the nomogram had favorable predictive accuracy in both the training and validation sets. CONCLUSIONS: The prognostic nomogram created in our study provides an individualized diagnosis, remedy, and risk evaluation for survival in patients with bladder cancer and lung metastasis. The nomogram would therefore enable clinicians to make more precise treatment decisions for patients with bladder cancer and lung metastasis.

26Validation of survival prognostic models for non-small-cell lung cancer in stage- and age-specific groups.PubMed

Xiaofei Wang, Lin Gu, Ying Zhang, et al.
Lung Cancer. 2015 Nov;90(2):281-7. doi: 10.1016/j.lungcan.2015.08.007. Epub 2015 Aug 18.
PURPOSE: Prognostic models have been proposed to predict survival for non-small-cell lung cancer (NSCLC). It is important to evaluate whether these models perform better than performance status (PS) alone in stage- and age-specific subgroups. PATIENTS AND METHODS: The validation cohort included 2060 stage I and 1611 stage IV NSCLC patients from 23CALGB studies. For stage I, Blanchon (B), Chansky (C) and Gail (G) models were evaluated along with the PS only model. For stage IV, Blanchon (B) and Mandrekar (M) models were compared with the PS only model. The c-index was used to assess the concordance between survival and risk scores. The c-index difference (c-difference) and the integrated discrimination improvement (IDI) were used to determine the improvement of these models over the PS only model. RESULTS: For stage I, B and PS have better survival separation. The c-index for B, PS, C and G are 0.61, 0.58, 0.57 and 0.52, respectively, and B performs significantly better than PS with c-difference=0.034. For stage IV, B, M and PS have c-index 0.61, 0.64 and 0.60, respectively; B and M perform significantly better than PS with c-difference=0.015 and 0.033, respectively. CONCLUSION: Although some prognostic models have better concordance with survival than the PS only model, the absolute improvement is small. More accurate prognostic models should be developed; the inclusion of tumor genetic variants may improve prognostic models.

27Radiomics and Dosiomics Signature From Whole Lung Predicts Radiation Pneumonitis: A Model Development Study With Prospective External Validation and Decision-curve Analysis.PubMed

Zhen Zhang, Zhixiang Wang, Meng Yan, et al.
Int J Radiat Oncol Biol Phys. 2023 Mar 1;115(3):746-758. doi: 10.1016/j.ijrobp.2022.08.047. Epub 2022 Aug 27.
PURPOSE: Radiation pneumonitis (RP) is one of the common side effects of radiation therapy in the thoracic region. Radiomics and dosiomics quantify information implicit within medical images and radiation therapy dose distributions. In this study we demonstrate the prognostic potential of radiomics, dosiomics, and clinical features for RP prediction. METHODS AND MATERIALS: Radiomics, dosiomics, dose-volume histogram (DVH) metrics, and clinical parameters were obtained on 314 retrospectively collected and 35 prospectively enrolled patients diagnosed with lung cancer between 2013 to 2019. A radiomics risk score (R score) and dosiomics risk score (D score), as well as a DVH-score, were calculated based on logistic regression after feature selection. Six models were built using different combinations of R score, D score, DVH score, and clinical parameters to evaluate their added prognostic power. Overoptimism was evaluated by bootstrap resampling from the training set, and the prospectively collected cohort was used as the external test set. Model calibration and decision-curve characteristics of the best-performing models were evaluated. For ease of further evaluation, nomograms were constructed for selected models. RESULTS: A model built by integrating all of the R score, D score, and clinical parameters had the best discriminative ability with areas under the curve of 0.793 (95% confidence interval [CI], 0.735-0.851), 0.774 (95% CI, 0.762-0.786), and 0.855 (95% CI, 0.719-0.990) in the training, bootstrapping, and external test sets, respectively. The calibration curve image showed good agreement between the predicted and actual values, with a slope of 1.21 and intercept of -0.04. The decision curve image showed a positive net benefit for the final model based on the nomogram. CONCLUSIONS: Radiomic and dosiomic features have the potential to assist with the prediction of RP, and the combination of radiomics, dosiomics, and clinical parameters led to the best prognostic model in the present study.

28Habitat radiomics and deep learning fusion nomogram to predict EGFR mutation status in stage I non-small cell lung cancer: a multicenter study.PubMed

Jingran Wu, Hao Meng, Lin Zhou, et al.
Sci Rep. 2024 Jul 10;14(1):15877. doi: 10.1038/s41598-024-66751-1.
Develop a radiomics nomogram that integrates deep learning, radiomics, and clinical variables to predict epidermal growth factor receptor (EGFR) mutation status in patients with stage I non-small cell lung cancer (NSCLC). We retrospectively included 438 patients who underwent curative surgery and completed driver-gene mutation tests for stage I NSCLC from four academic medical centers. Predictive models were established by extracting and analyzing radiomic features in intratumoral, peritumoral, and habitat regions of CT images to identify EGFR mutation status in stage I NSCLC. Additionally, three deep learning models based on the intratumoral region were constructed. A nomogram was developed by integrating representative radiomic signatures, deep learning, and clinical features. Model performance was assessed by calculating the area under the receiver operating characteristic (ROC) curve. The established habitat radiomics features demonstrated encouraging performance in discriminating between EGFR mutant and wild-type, with predictive ability superior to other single models (AUC 0.886, 0.812, and 0.790 for the training, validation, and external test sets, respectively). The radiomics-based nomogram exhibited excellent performance, achieving the highest AUC values of 0.917, 0.837, and 0.809 in the training, validation, and external test sets, respectively. Decision curve analysis (DCA) indicated that the nomogram provided a higher net benefit than other radiomics models, offering valuable information for treatment.

29Neoadjuvant Chemoimmunotherapy for NSCLC: A Systematic Review and Meta-Analysis.PubMed

Mark Sorin, Connor Prosty, Louis Ghaleb, et al.
JAMA Oncol. 2024 May 1;10(5):621-633. doi: 10.1001/jamaoncol.2024.0057.
IMPORTANCE: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%. OBJECTIVE: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials. DATA SOURCES: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients. STUDY SELECTION: Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded. MAIN OUTCOMES AND MEASURES: Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis. RESULTS: Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%). CONCLUSION AND RELEVANCE: This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.

30Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial.PubMed

Qing Zhou, Yi Pan, Xuening Yang, et al.
Cancer Cell. 2024 Jul 8;42(7):1258-1267.e2. doi: 10.1016/j.ccell.2024.05.024. Epub 2024 Jun 20.
We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 with or without chemotherapy, followed by surgery or radiotherapy, and then consolidation SHR-1701 in unresectable stage III non-small-cell lung cancer (NSCLC). In the primary cohort of patients receiving neoadjuvant combination therapy (n = 97), both primary endpoints were met, with a post-induction objective response rate of 58% (95% confidence interval [CI] 47-68) and an 18-month event-free survival (EFS) rate of 56.6% (95% CI 45.2-66.5). Overall, 27 (25%) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) major pathological responses and seven (26%) pathological complete responses were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2-86.7) in surgical patients and 57.3% (43.0-69.3) in radiotherapy-treated patients. Neoadjuvant SHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising efficacy with a tolerable safety profile in unresectable stage III NSCLC. Surgical conversion was feasible in a notable proportion of patients and associated with better survival outcomes.

31Multimodal Prehabilitation for Lung Cancer Surgery: A Randomized Controlled Trial.PubMed

Vanessa Ferreira, Enrico Maria Minnella, Rashami Awasthi, et al.
Ann Thorac Surg. 2021 Nov;112(5):1600-1608. doi: 10.1016/j.athoracsur.2020.11.022. Epub 2020 Dec 13.
BACKGROUND: The study was conducted to determine whether a multimodal prehabilitation program enhances postoperative functional recovery compared with multimodal rehabilitation. METHODS: Patients scheduled for non-small cell lung cancer resection were randomized to 2 groups receiving home-based moderate-intensity exercise, nutritional counseling with whey protein supplementation, and anxiety-reducing strategies for 4 weeks before the operation (PREHAB, n = 52) or 8 weeks after (REHAB, n = 43). Functional capacity (FC) was measured by the 6-minute walk test (6MWT) at baseline, immediately before the operation, and 4 and 8 weeks after operation. All patients were treated according to enhanced recovery pathway guidelines. RESULTS: There was no difference in FC at any point during the perioperative period between the 2 multimodal programs. By 8 weeks after operation, both groups returned to baseline FC, and a similar proportion of patients (>75%) in both groups had recovered to their baseline. CONCLUSIONS: In patients undergoing surgical resection for lung cancer within the context of an enhanced recovery pathway, multimodal prehabilitation initiated 4 weeks before operation is as effective in recovering FC as multimodal rehabilitation.

32Rationale for concurrent chemoradiotherapy for patients with stage III non-small-cell lung cancer.PubMed

John Conibear
Br J Cancer. 2020 Dec;123(Suppl 1):10-17. doi: 10.1038/s41416-020-01070-6.
When treating patients with unresectable stage III non-small-cell lung cancer (NSCLC), those with a good performance status and disease measured within a radical treatment volume should be considered for definitive concurrent chemoradiotherapy (cCRT). This guidance is based on key scientific rationale from two large Phase 3 randomised studies and meta-analyses demonstrating the superiority of cCRT over sequential (sCRT). However, the efficacy of cCRT comes at the cost of increased acute toxicity versus sequential treatment. Currently, there are several documented approaches that are addressing this drawback, which this paper outlines. At the point of diagnosis, a multidisciplinary team (MDT) approach can enable accurate assessment of patients, to determine the optimal treatment strategy to minimise risks. In addition, reviewing the Advisory Committee on Radiation Oncology Practice (ACROP) guidelines can provide clinical oncologists with additional recommendations for outlining target volume and organ-at-risk delineation for standard clinical scenarios in definitive cCRT (and adjuvant radiotherapy). Furthermore, modern advances in radiotherapy treatment planning software and treatment delivery mean that radiation oncologists can safely treat substantially larger lung tumours with higher radiotherapy doses, with greater accuracy, whilst minimising the radiotherapy dose to the surrounding healthy tissues. The combination of these advances in cCRT may assist in creating comprehensive strategies to allow patients to receive potentially curative benefits from treatments such as immunotherapy, as well as minimising treatment-related risks.

33Advances and challenges in the treatment of lung cancer.PubMed

Yuting Li, Bingshuo Yan, Shiming He
Biomed Pharmacother. 2023 Dec 31;169:115891. doi: 10.1016/j.biopha.2023.115891. Epub 2023 Nov 16.
Lung cancer accounts for a relatively high proportion of malignant tumors. As the most prevalent type of lung cancer, non-small cell lung cancer (NSCLC) is characterized by high morbidity and mortality. Presently, the arsenal of treatment strategies encompasses surgical resection, chemotherapy, targeted therapy and radiotherapy. However, despite these options, the prognosis remains distressingly poor with a low 5-year survival rate. Therefore, it is urgent to pursue a paradigm shift in treatment methodologies. In recent years, the advent of sophisticated biotechnologies and interdisciplinary integration has provided innovative approaches for the treatment of lung cancer. This article reviews the cutting-edge developments in the nano drug delivery system, molecular targeted treatment system, photothermal treatment strategy, and immunotherapy for lung cancer. Overall, by systematically summarizing and critically analyzing the latest progress and current challenges in these treatment strategies of lung cancer, we aim to provide a theoretical basis for the development of novel drugs for lung cancer treatment, and thus improve the therapeutic outcomes for lung cancer patients.

34Adjuvant Treatments for Surgically Resected Non-Small Cell Lung Cancer Harboring EGFR Mutations: A Review.PubMed

Antonio Passaro, Tony S K Mok, Ilaria Attili, et al.
JAMA Oncol. 2023 Aug 1;9(8):1124-1131. doi: 10.1001/jamaoncol.2023.0459.
IMPORTANCE: The use of adjuvant chemotherapy for stage IB-IIIA resected non-small cell lung cancer (NSCLC) has limited benefit for improving cure rates. The proportion of epidermal growth factor receptor (EGFR) alterations among patients with resected NSCLC is comparable to that observed in patients with advanced disease, and the use of EGFR tyrosine kinase inhibitors (TKIs) has been demonstrated to prolong disease-free survival (DFS). With recent approval of osimertinib in this context, a focus on the rapidly evolving scenario and future perspective in clinical practice is needed and was the aim of the current review. OBSERVATIONS: Randomized phase 3 clinical trials demonstrated DFS benefit with adjuvant EGFR TKI therapy in patients with resected EGFR mutation-positive NSCLC. The most recent trial (ADAURA) assessed 3-year adjuvant osimertinib and showed consistent DFS benefit and a significant role of the intervention in preventing the occurrence of brain metastasis. However, the role of adjuvant chemotherapy, the appropriate duration of treatment, the management of disease relapse, and the effective cure rate remain undetermined. A deeper investigation on molecular biomarkers, covariant patterns, and dynamic monitoring of postsurgical circulating DNA would be helpful for the implementation of future strategies to further improve survival rates after adjuvant therapy for EGFR mutation-positive NSCLC. CONCLUSIONS AND RELEVANCE: Adjuvant osimertinib revolutionized the treatment algorithm for patients with stage IB-IIIA resected EGFR mutation-positive NSCLC. Further evidence driven by clinical issues will be key for further optimization of the goals of adjuvant treatment in these patients.

35Alectinib in Resected -Positive Non-Small-Cell Lung Cancer.PubMed

Yi-Long Wu, Rafal Dziadziuszko, Jin Seok Ahn, et al.
N Engl J Med. 2024 Apr 11;390(14):1265-1276. doi: 10.1056/NEJMoa2310532.
BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, -positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected -positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, -positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected -positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

36Cost-effectiveness of Osimertinib as First-line Treatment and Sequential Therapy for EGFR Mutation-positive Non-small Cell Lung Cancer in China.PubMed

Hongfu Cai, Longfeng Zhang, Na Li, et al.
Clin Ther. 2019 Feb;41(2):280-290. doi: 10.1016/j.clinthera.2018.12.007. Epub 2019 Jan 11.
PURPOSE: This study aimed to evaluate the cost-effectiveness of osimertinib with gefitinib or erlotinib as first-line and sequential therapy for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in China. METHODS: The Markov model was used, and the study included 3 health states over a 10-year period. Transition probabilities and safety data were collected from the FLAURA (AZD9291 versus gefitinib or erlotinib in patients with locally advanced or metastatic Non-small Cell Lung Cancer) trial. Cost and utility values were derived from local charges and literature. Sensitivity analyses were performed to observe model stability. FINDINGS: The strategy with gefitinib or erlotinib first-line therapy and second-line gene-guided osimertinib therapy (GE-T790M) resulted in a gain of 0.31 quality-adjusted life year (QALY) at a cost of $15,200.95 per patient compared with the gefitinib or erlotinib first-line therapy and second-line chemotherapy (GE-chemotherapy). The incremental QALY and incremental cost values for first-line osimertinib therapy compared with GE-chemotherapy was 0.96 and $69,420.76, respectively. Compared with the GE-T790M strategy (0.96 QALY and $29,223.33), first-line osimertinib was estimated to be more effective (1.61 QALYs) and more costly ($83,443.14). Relative to the GE-chemotherapy strategy, the incremental cost-effectiveness ratios were $47,873.96 and $71,954.08 per QALY gained with GE-T790M and the osimertinib first-line strategy. The incremental cost-effectiveness ratio for first-line osimertinib versus GE-T790M was estimated to be $83,766.61. The results were found to be robust for univariate and multivariable sensitivity analyses. IMPLICATIONS: Gefitinib or erlotinib first-line and chemotherapy second-line strategies were the most cost-effective first-line treatments for EGFR mutations in patients with NSCLC. Gefitinib or erlotinib first-line and gene-guided osimertinib second-line strategies were more cost-effective than osimertinib first-line treatment for patients who preferred osimertinib administration in China.

37First-Line Immunotherapy for Non-Small-Cell Lung Cancer.PubMed

Martin Reck, Jordi Remon, Matthew D Hellmann
J Clin Oncol. 2022 Feb 20;40(6):586-597. doi: 10.1200/JCO.21.01497. Epub 2022 Jan 5.
For patients with metastatic non-small-cell lung cancer (mNSCLC), the last decade has been characterized by critical progress that has contributed to substantially improved survival. In particular, the development of specific antibodies against the programmed death (PD-1) receptor, programmed death-ligand 1 (PD-L1), and the cytotoxic T-lymphocyte-associated protein 4 receptor in the therapeutic strategy of mNSCLC either in first- or in second-line settings have led to unprecedented prolonged survival for a proportion of these patients. Although clinical development of immune checkpoint inhibitors with anti-PD-1 and PD-L1 therapies largely began as monotherapy in the second-line setting, the more recent progress has shifted toward combination approaches in first-line settings as well as the integration of immunotherapy into the clinical paradigm in earlier stages. Today, with the exception of mNSCLC harboring targetable oncogenes, nearly all patients with mNSCLC receive PD-1 or PD-L1 therapy in first-line settings. Here we report the current status of first-line immunotherapy in mNSCLC together with current challenges in selecting the best immunotherapeutic approach for the individual patient.

38Pembrolizumab for the treatment of non-small-cell lung cancer.PubMed

Edward B Garon, Naiyer A Rizvi, Rina Hui, et al.
N Engl J Med. 2015 May 21;372(21):2018-28. doi: 10.1056/NEJMoa1501824. Epub 2015 Apr 19.
BACKGROUND: We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS: We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS: Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).

39Sequential or combined immune checkpoint inhibitors and targeted therapy: Navigating uncharted waters.PubMed

K El Husseini, M Wislez
Respir Med Res. 2021 May;79:100820. doi: 10.1016/j.resmer.2021.100820. Epub 2021 Apr 1.

40Sequential therapy with ramucirumab and/or checkpoint inhibitors for non-small-cell lung cancer in routine practice.PubMed

Cliff Molife, Lisa M Hess, Zhanglin Lin Cui, et al.
Future Oncol. 2019 Sep 1;15(25):2915-2931. doi: 10.2217/fon-2018-0876. Epub 2019 Feb 22.
To describe treatment patterns and outcomes for advanced/metastatic non-small-cell lung cancer (aNSCLC) treated with single-agent or combination ramucirumab (ramucirumab-based) and/or immune checkpoint inhibitor (ICI-based) therapy. Retrospective study of aNSCLC patients (n = 4054) identified in the Flatiron Health database, who received at least two treatment lines including ramucirumab- and/or ICI-based regimens between December 2014 and May 2017. Median overall survival (95% CI) from aNSCLC diagnosis was 29.3 (25.5-33.0) months for patients receiving sequential ramucirumab- and ICI-based therapy (n = 245), 15.1 (12.6-18.2) months for patients receiving sequences including ramucirumab- without ICI-based therapy (n = 112), and 23.1 (21.9-24.2) months for patients receiving ICI-based therapy without ramucirumab-based therapy in sequence (n = 3697). Results provide real-world survival estimates for aNSCLC treated with sequences including ramucirumab- and/or ICI-based therapies.

41Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.PubMed

Julie Brahmer, Karen L Reckamp, Paul Baas, et al.
N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.
BACKGROUND: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS: We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS: The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

42Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery.PubMed

Joe Y Chang, Reza J Mehran, Lei Feng, et al.
Lancet Oncol. 2021 Oct;22(10):1448-1457. doi: 10.1016/S1470-2045(21)00401-0. Epub 2021 Sep 13.
BACKGROUND: A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND). METHODS: This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992. FINDINGS: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis. INTERPRETATION: Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended. FUNDING: Varian Medical Systems and US National Cancer Institute (National Institutes of Health).

43Comparative effectiveness of surgery and radiosurgery for stage I non-small cell lung cancer.PubMed

James B Yu, Pamela R Soulos, Laura D Cramer, et al.
Cancer. 2015 Jul 15;121(14):2341-9. doi: 10.1002/cncr.29359. Epub 2015 Apr 6.
BACKGROUND: Although surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC), stereotactic body radiotherapy (SBRT) has been disseminated as an alternative therapy. The comparative mortalities and toxicities of these treatments for patients of different life expectancies are unknown. METHODS: The Surveillance, Epidemiology, and End Results-Medicare linked database was used to identify patients who were 67 years old or older and underwent SBRT or surgery for stage I NSCLC from 2007 to 2009. Matched patients were stratified into short life expectancies (<5 years) and long life expectancies (≥5 years). Mortality and complication rates were compared with Poisson regression. RESULTS: Overall, 367 SBRT patients and 711 surgery patients were matched. Acute toxicity (0-1 month) was lower from SBRT versus surgery (7.9% vs 54.9%, P < .001). At 24 months after treatment, there was no difference (69.7% vs 73.9%, P = .31). The incidence rate ratio (IRR) for toxicity from SBRT versus surgery was 0.74 (95% confidence interval [CI], 0.64-0.87). Overall mortality was lower with SBRT versus surgery at 3 months (2.2% vs 6.1%, P = .005), but by 24 months, overall mortality was higher with SBRT (40.1% vs 22.3%, P < .001). For patients with short life expectancies, there was no difference in lung cancer mortality (IRR, 1.01; 95% CI, 0.40-2.56). However, for patients with long life expectancies, there was greater overall mortality (IRR, 1.49; 95% CI, 1.11-2.01) as well as a trend toward greater lung cancer mortality (IRR, 1.63; 95% CI, 0.95-2.79) with SBRT versus surgery. CONCLUSIONS: SBRT was associated with lower immediate mortality and toxicity in comparison with surgery. However, for patients with long life expectancies, there appears to be a relative benefit from surgery versus SBRT.

44Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment.PubMed

Narjust Duma, Rafael Santana-Davila, Julian R Molina
Mayo Clin Proc. 2019 Aug;94(8):1623-1640. doi: 10.1016/j.mayocp.2019.01.013.
Lung cancer remains the leading cause of cancer deaths in the United States. In the past decade, significant advances have been made in the science of non-small cell lung cancer (NSCLC). Screening has been introduced with the goal of early detection. The National Lung Screening Trial found a lung cancer mortality benefit of 20% and a 6.7% decrease in all-cause mortality with the use of low-dose chest computed tomography in high-risk individuals. The treatment of lung cancer has also evolved with the introduction of several lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations. Similarly, immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of NSCLC treatment. Furthermore, the results of new trials continue to help us understand the role of these novel agents and which patients are more likely to benefit; ICIs are now part of the first-line NSCLC treatment armamentarium as monotherapy, combined with chemotherapy, or after definite chemoradiotherapy in patients with stage III unresectable NSCLC. Expression of programmed cell death protein-ligand 1 in malignant cells has been studied as a potential biomarker for response to ICIs. However, important drawbacks exist that limit its discriminatory potential. Identification of accurate predictive biomarkers beyond programmed cell death protein-ligand 1 expression remains essential to select the most appropriate candidates for ICI therapy. Many questions remain unanswered regarding the proper sequence and combinations of these new agents; however, the field is moving rapidly, and the overall direction is optimistic.

45Comparative Effectiveness of Atezolizumab, Nivolumab, and Docetaxel in Patients With Previously Treated Non-Small Cell Lung Cancer.PubMed

Sreeram Ramagopalan, Alind Gupta, Paul Arora, et al.
JAMA Netw Open. 2021 Nov 1;4(11):e2134299. doi: 10.1001/jamanetworkopen.2021.34299.
IMPORTANCE: Evidence regarding real-world effectiveness of therapies for patients with advanced non-small cell lung cancer (NSCLC) whose tumors are resistant to platinum-based chemotherapy is lacking. OBJECTIVE: To compare the effectiveness of the immune checkpoint inhibitors atezolizumab (programmed cell death ligand 1 inhibitor) and nivolumab (programmed cell death 1 inhibitor) and the chemotherapy drug docetaxel in patients with advanced NSCLC resistant to platinum-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study compared patients aged 18 years or older with advanced NSCLC who initiated atezolizumab, docetaxel, or nivolumab and who had previously been exposed to platinum-based chemotherapy using nationally representative real-world data from more than 280 US cancer clinics. Patients were followed-up from May 2011 to March 2020. Data analysis was performed between April and June 2021. Comparisons of interest were between atezolizumab vs docetaxel and atezolizumab vs nivolumab. EXPOSURES: Initiation of atezolizumab, nivolumab, or docetaxel monotherapy. MAIN OUTCOME AND MEASURES: The main outcome was overall survival (OS). RESULTS: A total of 3336 patients (mean [SD] age, 67.1 [9.49] years; 1820 [54.6%] men and 1516 [45.4%] women) were assessed in the main analysis, including 206 patients receiving atezolizumab, 500 receiving docetaxel, and 2630 receiving nivolumab. Patients receiving atezolizumab were older than those treated with docetaxel (mean age [SD], 68.3 [9.4] years vs 65.6 [9.5] years), and were more likely to have been treated in an academic setting (39 patients [18.9%]) than those receiving docetaxel (49 patients [9.8%]) and nivolumab (128 patients [4.9%]). After adjustment for baseline characteristics, atezolizumab was associated with a significantly longer OS compared with docetaxel (adjusted hazard ratio [aHR], 0.79; 95% CI, 0.64-0.97). No significant difference in OS was observed between atezolizumab and nivolumab (aHR, 1.07; 95% CI, 0.89-1.28). These findings were consistent across all patient subgroups tested, and robust to plausible deviations from random missingness for Eastern Cooperative Oncology Group performance status in real-world data (eg, the tipping point for loss of a significantly beneficial effect for atezolizumab vs docetaxel was achieved if patients in the docetaxel group missing baseline Eastern Cooperative Oncology Group performance status had a mean performance status of 1.43 higher than expected). CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study, atezolizumab was superior to docetaxel and matched nivolumab in prolonging OS in a real-world cohort of patients with advanced NSCLC who previously received platinum-based chemotherapy.

46Efficacy and safety of immune checkpoint inhibitors for advanced non-small cell lung cancer with or without PD-L1 selection: A systematic review and network meta-analysis.PubMed

Yan Li, Xueyan Liang, Huijuan Li, et al.
Chin Med J (Engl). 2023 Sep 20;136(18):2156-2165. doi: 10.1097/CM9.0000000000002750. Epub 2023 Aug 18.
BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer (NSCLC); however, evidence regarding their relative efficacy and safety is lacking. This study compared the efficacy and safety of all currently available ICI treatments in patients with advanced NSCLC to identify optimal treatment regimens. METHODS: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase databases were systematically searched for randomized controlled trials (RCTs) published up to August 8, 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR) and adverse events (AEs). RESULTS: Forty RCTs involving 22,526 patients were selected, and a total of 26 treatment regimens were identified. Treatment with anti-programmed cell death protein-1 (anti-PD-1) provided superior OS compared with anti-programmed death ligand 1 (anti-PD-L1) treatment. ICIs plus platinum-based chemotherapy (PBC) were superior to ICIs treatment alone, although the addition of PBC increased treatment toxicity. Cemiplimab ranked first for OS and lowest for any-grade AEs in advanced NSCLC patients without PD-L1 selection. Regarding grade ≥3 AEs, the toxicity of ICI monotherapy or ICI-ICI combination was consistently lower than that of the other treatments. For patients without PD-L1 selection, cemiplimab showed the best OS, pembrolizumab plus docetaxel (Pem-DXT) showed the best PFS, and atezolizumab plus bevacizumab and PBC (Atezo-Beva-PBC) showed the best ORR. Pembrolizumab plus PBC and Atezo-Beva-PBC were the most likely optimal treatments for OS and PFS in patients with PD-L1 expression <1%, respectively. In patients with PD-L1 expression ≥1%, treatment regimens containing anti-PD-1 provided superior OS benefits compared with those of anti-PD-L1 treatment, and sintilimab plus PBC (Sint-PBC) provided the best OS benefit; as for PFS, ICI plus PBC consistently showed greater PFS benefits than ICI or PBC alone. For patients with anti-PD-L1 expression of 1-49%, camrelizumab plus PBC provided the best benefit for OS and PFS among included treatment. Durvalumab-tremelimumab-PBC and Atezo-Beva-PBC respectively presented the highest OS and PFS for patients with PD-L1 expression ≥50%. Moreover, cemiplimab and Atezo-Beva-PBC yielded the best OS and PFS benefits as first-line treatments for patients with advanced NSCLC, respectively. CONCLUSIONS: Although ICI plus PBC likely resulted in superior survival outcomes compared to ICI treatment alone, it did increase toxicity. Cemiplimab presented a well-balanced efficacy and safety profile in advanced NSCLC treatment. Our findings with the current ICIs comparisons will aid future trials for cancer immunotherapy. REGISTRATION: PROSPERO, https://www.crd.york.ac.uk/PROSPERO/ , CRD42022323879.

47A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer.PubMed

Jeremy P Harris, Manali I Patel, Billy W Loo, et al.
Lung Cancer. 2017 Jun;108:173-182. doi: 10.1016/j.lungcan.2017.03.017. Epub 2017 Mar 29.
OBJECTIVES: In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged ≥65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach. RESULTS: 1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide. CONCLUSION: Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.

48Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study.PubMed

Myung-Ju Ahn, Kentaro Tanaka, Luis Paz-Ares, et al.
J Clin Oncol. 2025 Jan 20;43(3):260-272. doi: 10.1200/JCO-24-01544. Epub 2024 Sep 9.
PURPOSE: The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC). METHODS: Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points. RESULTS: In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively. CONCLUSION: Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

49Mutation profile of non-small cell lung cancer revealed by next generation sequencing.PubMed

Ya-Sian Chang, Siang-Jyun Tu, Yu-Chia Chen, et al.
Respir Res. 2021 Jan 6;22(1):3. doi: 10.1186/s12931-020-01608-5.
BACKGROUND: Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have rarely been performed in these populations. METHOD: We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients. RESULTS: Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions. CONCLUSIONS: We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.

50Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer.PubMed

Sara S Fois, Panagiotis Paliogiannis, Angelo Zinellu, et al.
Int J Mol Sci. 2021 Jan 9;22(2):612. doi: 10.3390/ijms22020612.
Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely , , , , and mutations or amplification, as well as and fusions. Furthermore, we investigated the predictive impact of these alterations on the outcomes of modern targeted therapies, their global prognostic significance, and their mutual interaction in cases of co-occurrence.

51Opportunities and challenges of neoadjuvant targeted therapy in nonsmall cell lung cancer.PubMed

Ji'an Zou, Yue Zeng, Fang Wu
Curr Opin Oncol. 2023 Jan 1;35(1):22-30. doi: 10.1097/CCO.0000000000000914. Epub 2022 Nov 2.
PURPOSE OF REVIEW: The aim of this study is to summarize the completed and ongoing clinical trials of neoadjuvant targeted therapy, discuss tolerability and efficacy, and explain the role of neoadjuvant targeted therapy in patients with resectable nonsmall cell lung cancer (NSCLC). At the same time, the existing challenges are presented, including assessment methods, biomarkers, surrogate endpoints and so on. We also put forward our views on possible ways to make improvements and establish neoadjuvant therapy a standard treatment in resectable NSCLC. RECENT FINDINGS: The mortality of lung cancer has decreased in the last 10 years, which can partly be attributed to advancement of targeted therapy. Targeted therapy has become the first-line treatment for patients with advanced mutation gene positive NSCLC, achieving the effect of prolonging overall survival (OS). Compared with chemotherapy, targeted therapy is associated with good tolerability and high response rate. Neoadjuvant targeted therapy has emerged in recent years and attracted attention of researchers. Early findings proved that neoadjuvant targeted therapy alone can improve patients' disease-free survival (DFS) and the efficacy of combining with other forms of neoadjuvant therapy is also being explored by researchers. SUMMARY: Neoadjuvant targeted therapy is playing an important role in NSCLC and worth more in-depth research.

52Real-world prevalence of programmed death ligand 1 expression in locally advanced or metastatic non-small-cell lung cancer: The global, multicenter EXPRESS study.PubMed

M Dietel, N Savelov, R Salanova, et al.
Lung Cancer. 2019 Aug;134:174-179. doi: 10.1016/j.lungcan.2019.06.012. Epub 2019 Jun 12.
OBJECTIVES: Tumor programmed death ligand 1 (PD-L1) expression is associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicenter, retrospective observational study to determine real-world prevalence of tumor PD-L1 expression in patients with NSCLC. MATERIALS AND METHODS: Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumor tissue block (≤5 years old) obtained before treatment were identified in 45 centers across 18 countries. Tumor samples from eligible patients were selected consecutively, when possible. PD-L1 expression was evaluated at each center using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). RESULTS: Of 2617 patients who met inclusion criteria, 2368 (90%) had PD-L1 data; 530 (22%) patients had PD-L1 TPS ≥ 50%, 1232 (52%) had PD-L1 TPS ≥ 1%, and 1136 (48%) had PD-L1 TPS < 1%. The most common reason for not having PD-L1 data (n = 249) was insufficient tumor cells (<100) on the slide (n = 170 [6%]). Percentages of patients with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively were: 22%/52% in Europe; 22%/53% in Asia Pacific; 21%/47% in the Americas, and 24%/55% in other countries. Prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports from metastatic NSCLC studies. Among 1064 patients negative for both EGFR mutation and ALK alteration, the percentage with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively, were 27% and 53%. CONCLUSIONS: This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumor expression using the 22C3 pharmDx kit. Testing failure rate was low with local evaluation of PD-L1 TPS across a large number of centers. Prevalence of PD-L1 TPS ≥ 50% and TPS ≥ 1% among patients with stage IIIB/IV NSCLC was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations.

53Potential biomarkers for immunotherapy in non-small-cell lung cancer.PubMed

Xing Wang, Ziyun Qiao, Beatrice Aramini, et al.
Cancer Metastasis Rev. 2023 Sep;42(3):661-675. doi: 10.1007/s10555-022-10074-y. Epub 2023 May 1.
For individuals with advanced or metastatic non-small cell lung cancer (NSCLC), the primary treatment is platinum-based doublet chemotherapy. Immune checkpoint inhibitors (ICIs), primarily PD-1/PD-L1 and CTLA-4, have been found to be effective in patients with NSCLC who have no EGFR/ALK mutations. Furthermore, ICIs are considered a standard therapy. The quantity of fresh immunogenic antigens discovered by cytotoxic T cells was measured by PD-L1 expression and tumor mutational burden (TMB), which were the first biomarkers assessed in clinical trials. However, immunotherapy did not have response efficacy markers similar to targeted therapy, highlighting the significance of newly developed biomarkers. This investigation aims to review the research on immunotherapy for NSCLC, focusing primarily on the impact of biomarkers on efficacy prediction to determine whether biomarkers may be utilized to evaluate the effectiveness of immunotherapy.

54PD-L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non-small cell lung cancer?PubMed

Aoran Dong, Yiming Zhao, Zhihua Li, et al.
J Gene Med. 2021 Feb;23(2):e3294. doi: 10.1002/jgm.3294. Epub 2021 Jan 5.
PD-L1 and tumor mutation burden (TMB) are the most widely used immunotherapy biomarkers to identify populations who would attain clinical benefit, with the higher values predicting better therapeutic efficacy. This review addresses the predictive values and unresolved challenges of these two biomarkers. PD-1 and PD-L1 inhibitors have induced durable and effective responses in patients with advanced non-small cell lung cancer, confirmed by multiple clinical trials and real-world studies. Different clinical trials, involving both PD-1/PD-L1 inhibitors alone and combination regimens, adopted either PD-L1 or TMB to stratify the patients, although the predictive capabilities of these two biomarkers are different. In the first-line setting, PD-L1 of 50% or more as a cut-off value can help select candidates for pembrolizumab or atezolizumab monotherapy; however, these two biomarkers poorly predict the efficacy of immunotherapy combination regimens as first-line treatments. In the second-line setting, although patients can benefit from nivolumab regardless of PD-L1 expression, both PD-L1 and blood TMB can be used as biomarkers to find patients suitable for atezolizumab. Except for inaccurate predictiveness, there are many unresolved problems with regard to the two biomarkers, such as the lack of standard detection methods, and their susceptibilities to other dynamic changes. The predictive values of TMB and PD-L1 were low in most circumstances; however, PD-L1 expression greater than ≥ 50% can help select appropriate patients for pembrolizumab and atezolizumab, respectively, as first-line monotherapies. Higher PD-L1 or TMB was associated with greater efficacy for atezolizumab as a second-line monotherapy.

55Lung Cancer Staging and Prognosis.PubMed

Gavitt A Woodard, Kirk D Jones, David M Jablons
Cancer Treat Res. 2016;170:47-75. doi: 10.1007/978-3-319-40389-2_3.
The seventh edition of the non-small cell lung cancer (NSCLC) TNM staging system was developed by the International Association for the Staging of Lung Cancer (IASLC) Lung Cancer Staging Project by a coordinated international effort to develop data-derived TNM classifications with significant survival differences. Based on these TNM groupings, current 5-year survival estimates in NSLCC range from 73 % in stage IA disease to 13 % in stage IV disease. TNM stage remains the most important prognostic factor in predicting recurrence rates and survival times, followed by tumor histologic grade, and patient sex, age, and performance status. Molecular prognostication in lung cancer is an exploding area of research where interest has moved beyond TNM stage and into individualized genetic tumor analysis with immunohistochemistry, microarray, and mutation profiles. However, despite intense research efforts and countless publications, no molecular prognostic marker has been adopted into clinical use since most fail in subsequent cross-validation with few exceptions. The recent interest in immunotherapy for NSCLC has identified new biomarkers with early evidence that suggests that PD-L1 is a predictive marker of a good response to new immunotherapy drugs but a poor prognostic indicator of overall survival. Future prognostication of outcomes in NSCLC will likely be based on a combination of TNM stage and molecular tumor profiling and yield more precise, individualized survival estimates and treatment algorithms.

56Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing.PubMed

Hira Rizvi, Francisco Sanchez-Vega, Konnor La, et al.
J Clin Oncol. 2018 Mar 1;36(7):633-641. doi: 10.1200/JCO.2017.75.3384. Epub 2018 Jan 16.
Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number-altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P < .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number-altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.

57Phenotypic heterogeneity of potentially curable non-small-cell lung cancer: cohort study with cluster analysis.PubMed

Lama Sakr, David Small, Goulnar Kasymjanova, et al.
J Thorac Oncol. 2015 May;10(5):754-761. doi: 10.1097/JTO.0000000000000505.
INTRODUCTION: Significant differences in outcome are observed among lung cancer patients belonging to the same tumor node metastasis stage, suggesting phenotypic heterogeneity beyond this staging algorithm. We used a cluster analysis approach to classify patients into distinct phenotypes, and we attempted to validate the clinical relevance of these phenotypes by comparing outcome. METHODS: We formed a cohort of all stage I to III non-small-cell lung cancer patients seen between January 2004 and October 2010 in a cancer center and followed until death or last follow-up appointment, with prospectively collected data on clinical and tumor characteristics. Multiple correspondence analysis was followed by hierarchical clustering to form homogenous clusters of patients. Overall survival and disease-free survival estimates were compared among clusters. RESULTS: The cohort included 367 patients (mean follow-up of 2.5 years), 173 of whom died during that period (191 deaths per 1000 person-years). A four-cluster model was identified, revealing distinct phenotypes with respect to baseline characteristics. Hazard ratios for mortality were 8.1, 5.0, and 3.7 (all statistically significant) for clusters 2, 1, and 3, respectively, when compared with cluster 4-with the most favorable outcome. CONCLUSION: Staging of patients with non-small-cell lung cancer for prognostic purposes may be improved by considering phenotypes that exhibit significant differences in clinical course and outcome.

58A novel analytical framework for risk stratification of real-world data using machine learning: A small cell lung cancer study.PubMed

Luca Marzano, Adam S Darwich, Salomon Tendler, et al.
Clin Transl Sci. 2022 Oct;15(10):2437-2447. doi: 10.1111/cts.13371. Epub 2022 Jul 29.
In recent studies, small cell lung cancer (SCLC) treatment guidelines based on Veterans' Administration Lung Study Group limited/extensive disease staging and resulted in broad and inseparable prognostic subgroups. Evidence suggests that the eight versions of tumor, node, and metastasis (TNM) staging can play an important role to address this issue. The aim of the present study was to improve the detection of prognostic subgroups from a real-word data (RWD) cohort of patients and analyze their patterns using a development pipeline with thoracic oncologists and machine learning methods. The method detected subgroups of patients informing unsupervised learning (partition around medoids) including the impact of covariates on prognosis (Cox regression and random survival forest). An analysis was carried out using patients with SCLC (n = 636) with stage IIIA-IVB according to TNM classification. The analysis yielded k = 7 compacted and well-separated clusters of patients. Performance status (Eastern Cooperative Oncology Group-Performance Status), lactate dehydrogenase, spreading of metastasis, cancer stage, and CRP were the baselines that characterized the subgroups. The selected clustering method outperformed standard clustering techniques, which were not capable of detecting meaningful subgroups. From the analysis of cluster treatment decisions, we showed the potential of future RWD applications to understand disease, develop individualized therapies, and improve healthcare decision making.

59In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data.PubMed

Yalan Tong, Xiaosha Wan, Chang Yin, et al.
BMC Cancer. 2024 Oct 23;24(1):1305. doi: 10.1186/s12885-024-13071-2.
BACKGROUND: There is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate. METHODS: We initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs). Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021. RESULTS: The bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69-0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61-0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188). CONCLUSIONS: Research on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

60A Machine Learning Model Based on PET/CT Radiomics and Clinical Characteristics Predicts Tumor Immune Profiles in Non-Small Cell Lung Cancer: A Retrospective Multicohort Study.PubMed

Haipeng Tong, Jinju Sun, Jingqin Fang, et al.
Front Immunol. 2022 Apr 29;13:859323. doi: 10.3389/fimmu.2022.859323. eCollection 2022.
BACKGROUND: The tumor immune microenvironment (TIME) phenotypes have been reported to mainly impact the efficacy of immunotherapy. Given the increasing use of immunotherapy in cancers, knowing an individual's TIME phenotypes could be helpful in screening patients who are more likely to respond to immunotherapy. Our study intended to establish, validate, and apply a machine learning model to predict TIME profiles in non-small cell lung cancer (NSCLC) by using F-FDG PET/CT radiomics and clinical characteristics. METHODS: The RNA-seq data of 1145 NSCLC patients from The Cancer Genome Atlas (TCGA) cohort were analyzed. Then, 221 NSCLC patients from Daping Hospital (DPH) cohort receivedF-FDG PET/CT scans before treatment and CD8 expression of the tumor samples were tested. The Artificial Intelligence Kit software was used to extract radiomic features of PET/CT images and develop a radiomics signature. The models were established by radiomics, clinical features, and radiomics-clinical combination, respectively, the performance of which was calculated by receiver operating curves (ROCs) and compared by DeLong test. Moreover, based on radiomics score (Rad-score) and clinical features, a nomogram was established. Finally, we applied the combined model to evaluate TIME phenotypes of NSCLC patients in The Cancer Imaging Archive (TCIA) cohort (n = 39). RESULTS: TCGA data showed CD8 expression could represent the TIME profiles in NSCLC. In DPH cohort, PET/CT radiomics model outperformed CT model (AUC: 0.907 vs. 0.861, = 0.0314) to predict CD8 expression. Further, PET/CT radiomics-clinical combined model (AUC = 0.932) outperformed PET/CT radiomics model (AUC = 0.907, = 0.0326) or clinical model (AUC = 0.868, = 0.0036) to predict CD8 expression. In the TCIA cohort, the predicted CD8-high group had significantly higher immune scores and more activated immune pathways than the predicted CD8-low group ( = 0.0421). CONCLUSION: Our study indicates that F-FDG PET/CT radiomics-clinical combined model could be a clinically practical method to non-invasively detect the tumor immune status in NSCLCs.

61An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance.PubMed

Lauren Averett Byers, Lixia Diao, Jing Wang, et al.
Clin Cancer Res. 2013 Jan 1;19(1):279-90. doi: 10.1158/1078-0432.CCR-12-1558. Epub 2012 Oct 22.
PURPOSE: Epithelial-mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non-small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study. EXPERIMENTAL DESIGN: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified. RESULTS: Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies. CONCLUSION: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype.

62Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.PubMed

Takashi Shintani, Noriko Kishi, Yukinori Matsuo, et al.
Clin Lung Cancer. 2021 Sep;22(5):401-410. doi: 10.1016/j.cllc.2021.01.017. Epub 2021 Feb 4.
INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors. MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP. RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007). CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.

63Analysis of the risk factors of radiation pneumonitis and the predictive ability of dosiomics in non-small-cell lung cancer.PubMed

Lei Zhuang, Xue Bai, Ying Chen, et al.
Future Oncol. 2023 Oct;19(32):2157-2169. doi: 10.2217/fon-2023-0316. Epub 2023 Oct 27.
This prospective study investigated the incidence of radiation pneumonitis (RP) after immunotherapy followed by radiotherapy in non-small-cell lung cancer, analyzed the risk factors for RP, and explored the predictive performance of dosimetry and dosiomics. Risk factors for grade ≥2 RP were calculated by using a logistic regression model. Predictive performance was compared on the basis of area under the curve values. Grade ≥2 RP occurred in 16 cases (26.7%). The AUC values of V, gray-level dependence matrix-small dependence high gray-level emphasis (GLDM-SDHGLE) and combined features were 0.685, 0.724 and 0.734, respectively. Smoking history, bilateral lung V and GLDM-SDHGLE were independent risk factors for RP. Dosiomics can effectively predict RP.

64Radiation pneumonitis after concurrent aumolertinib and thoracic radiotherapy in EGFR-mutant non-small cell lung cancer patients.PubMed

Hanjing Yin, Wenxiao Jia, Jinming Yu, et al.
BMC Cancer. 2024 Feb 12;24(1):197. doi: 10.1186/s12885-024-11946-y.
BACKGROUND: The superior efficacy of concurrent thoracic radiotherapy (TRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been proven in locally advanced and advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, the high incidence of radiation pneumonitis (RP) reduced by concurrent TRT and TKIs has attracted widespread attention. Thus, this study was designed to investigate the rate and risk factors for RP in EGFR-positive NSCLC patients simultaneously treated with aumolertinib and TRT. METHODS: We retrospectively evaluated stage IIIA-IVB NSCLC patients treated with concurrent aumolertinib and TRT between May 2020 and December 2022 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed by two senior radiologists and then graded from 1 to 5 according to the Common Terminology Criteria for Adverse Events v5.0. All risk factors were evaluated by univariate and multivariate logistic regression analyses. RESULTS: A total of 49 patients were included, the incidence of grade ≥ 2 RP was 42.9%. Grade 2 and 3 RP were observed in 28.6% and 14.3% of patients, respectively. Grade 4 to 5 RP were not observed. the gross total volume (GTV) ≥ 21 ml and ipsilateral lung V20 ≥ 25% were risk factors for RP. The median progression-free survival (PFS) in the first-line therapy group and second-line therapy group were 23.5 months and 17.2 months, respectively (p = 0.10). CONCLUSIONS: Better local control is achieved with concurrent TRT and aumolertinib, and special attention should be given to controlling ipsilateral lung V20 and GTV to reduce the risk of RP.

65Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer.PubMed

François Cousin, Colin Desir, Selma Ben Mustapha, et al.
Radiother Oncol. 2021 Apr;157:47-55. doi: 10.1016/j.radonc.2021.01.001. Epub 2021 Jan 14.
BACKGROUND AND PURPOSE: Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. Immune checkpoint inhibitors (ICIs) have recently been identified as potential causal agents of RRP but its real incidence and potential risk factors remain unknown. MATERIALS AND METHODS: Medical records and CTs of patients treated with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors for advanced lung cancer between 2014 and 2019 at our tertiary center, and who had a previous history of lung irradiation were retrospectively analyzed. We identified RRP as lung CT modifications occurring in the irradiation field >6 months after conventionally fractionated radiotherapy completion and >1 year after stereotactic body radiation therapy. Clinical and dosimetric data were analyzed to identify potential risk factors for RRP. RESULTS: Among 348 patients treated with ICIs, data from 80 eligible patients were analyzed (median age, 69 years [interquartile range, 11]; 45 men). Fifteen patients (18.8%) presented with RRP. Median time between end of radiotherapy and RRP was 450 days (range, 231-1859). No risk factor was significantly associated with RRP. ICI-related pneumonitis was associated with RRP in 33.3% of cases (p = 0.0021), developing either concomitantly or after RRP. Incidence of grade ≥ 3 pneumonitis in the RRP population was 13.3 %. CONCLUSION: We demonstrated a high incidence of RRP (18.8%) in our population of previously irradiated patients treated with ICIs for lung cancer. We identified no risk factors for RRP, but an association was noted between RRP and ICI-related pneumonitis.

66Risk factor analysis of the development of severe radiation pneumonitis in patients with non-small cell lung cancer treated with curative radiotherapy, with focus on underlying pulmonary disease.PubMed

Hakyoung Kim, Jeongeun Hwang, Sun Myung Kim, et al.
BMC Cancer. 2023 Oct 17;23(1):992. doi: 10.1186/s12885-023-11520-y.
BACKGROUND: We aim to identify the multifaceted risk factors that can affect the development of severe radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with curative high-dose radiotherapy with or without concurrent chemotherapy. METHODS: We retrospectively reviewed the medical records of 175 patients with stage-I-III NSCLC treated with curative thoracic X-ray radiotherapy at the Korea University Guro Hospital between June 2019 and June 2022. Treatment-related complications were evaluated using the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: The median follow-up duration was 15 months (range: 3-47 months). Idiopathic pulmonary fibrosis (IPF) as an underlying lung disease (P < 0.001) and clinical stage, regarded as the concurrent use of chemotherapy (P = 0.009), were associated with a high rate of severe RP. In multivariate analyses adjusting confounding variables, the presence of IPF as an underlying disease was significantly associated with severe RP (odds ratio [95% confidence interval] = 48.4 [9.09-347]; P < 0.001). In a subgroup analysis of stage-I-II NSCLC, the incidence of severe RP in the control, chronic obstructive pulmonary disease (COPD), and IPF groups was 3.2%, 4.3%, and 42.9%, respectively (P < 0.001). The incidence of severe RP was 15.2%, 10.7%, and 75.0% in the control, COPD, and IPF groups, respectively (P < 0.001) in the stage-III NSCLC group. CONCLUSIONS: This study revealed that IPF as an underlying lung disease and the concurrent use of chemotherapy are associated with a high rate of severe RP. In contrast, COPD did not increase the risk of pulmonary toxicity after receiving curative high-dose radiotherapy.

67The Timing, Trajectory, and Incidence of Immune-Related Adverse Events in NSCLC Treated With Atezolizumab.PubMed

Katherine E R Smith, Stephanie L Pritzl, Wei Yu, et al.
JTO Clin Res Rep. 2023 Nov 23;4(12):100611. doi: 10.1016/j.jtocrr.2023.100611. eCollection 2023 Dec.
INTRODUCTION: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors can have complicated clinical courses. We comprehensively evaluated the timing, trajectory, and incidence of both single and multiple irAEs for NSCLC treated with atezolizumab. METHODS: Data were pooled from 2457 patients who participated in the IMpower130, IMpower132, and IMpower150 clinical trials investigating the use of atezolizumab in metastatic NSCLC as part of a chemoimmunotherapy regimen. Longitudinal irAE data with landmark analysis, time-to-onset, changes in grading severity, and occurrence of multiple events were summarized. RESULTS: In general, 1557 patients were treated with atezolizumab and 900 patients were in the control groups. Median follow-up was 32.3 and 23.5 months, respectively. In the atezolizumab group, 753 patients (48.4%) experienced at least one irAE. In the control group, 289 patients (32.1%) experienced at least one nonimmune adverse event that was attributed to an irAE. In the atezolizumab group, the most common irAEs were rash, hepatitis, and hypothyroidism. Furthermore, 13% of the patients experienced two irAEs and 4% experienced three irAEs. Within 5 months of treatment, the cumulative incidence for any irAE was 39.2%. Median time-to-onset varied from 1 to 10 months based on the specific irAE. Grade 1 to 2 irAEs increased in severity for 33% of the patients. CONCLUSIONS: We identified dynamic clinical patterns for irAEs in patients treated with atezolizumab, including variations in time-to-onset, incidence of multiple irAEs, and frequency of irAEs increasing in severity. These results can guide clinical management and future reporting of adverse events to enable comprehensive longitudinal analyses.

68Immune Checkpoint Inhibitor-Associated Pneumonitis in Non-Small Cell Lung Cancer: Current Understanding in Characteristics, Diagnosis, and Management.PubMed

Qin Zhang, Liansha Tang, Yuwen Zhou, et al.
Front Immunol. 2021 May 28;12:663986. doi: 10.3389/fimmu.2021.663986. eCollection 2021.
Immunotherapy that includes programmed cell death-1 (PD-1), programmed cell death- ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors has revolutionized the therapeutic strategy in multiple malignancies. Although it has achieved significant breakthrough in advanced non-small cell lung cancer patients, immune-related adverse events (irAEs) including checkpoint inhibitor pneumonitis (CIP), are widely reported. As the particularly worrisome and potentially lethal form of irAEs, CIP should be attached more importance. Especially in non-small cell lung cancer (NSCLC) patients, the features of CIP may be more complicated on account of the overlapping respiratory signs compromised by primary tumor following immunotherapy. Herein, we included the previous relevant reports and comprehensively summarized the characteristics, diagnosis, and management of CIP. We also discussed the future direction of optimal steroid therapeutic schedule for patients with CIP in NSCLC based on the current evidence.

69Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.PubMed

John V Heymach, David Harpole, Tetsuya Mitsudomi, et al.
N Engl J Med. 2023 Nov 2;389(18):1672-1684. doi: 10.1056/NEJMoa2304875. Epub 2023 Oct 23.
BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the ) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS: A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented or alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).

70Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.PubMed

Shun Lu, Wei Zhang, Lin Wu, et al.
JAMA. 2024 Jan 16;331(3):201-211. doi: 10.1001/jama.2023.24735.
IMPORTANCE: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. OBJECTIVE: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. MAIN OUTCOMES AND MEASURES: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. RESULTS: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. CONCLUSIONS AND RELEVANCE: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04158440.

71Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related adverse events.PubMed

Alessio Cortellini, Melissa Bersanelli, Daniele Santini, et al.
Eur J Cancer. 2020 Mar;128:17-26. doi: 10.1016/j.ejca.2019.12.031. Epub 2020 Mar 5.
BACKGROUND: Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients. PATIENTS AND METHODS: We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI. RESULTS: One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients. CONCLUSIONS: Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

72Treatment response and safety of immunotherapy for advanced non-small cell lung cancer with comorbid chronic obstructive pulmonary disease: a retrospective cohort study.PubMed

Kening Zhang, Chengzhi Zhou, Jiabo Gao, et al.
Transl Lung Cancer Res. 2022 Nov;11(11):2306-2317. doi: 10.21037/tlcr-22-667.
BACKGROUND: Immunotherapy has provided a novel therapeutic option for lung cancer but studies involving patients with advanced non-small cell lung cancer (NSCLC) coupled with various degrees of comorbid chronic obstructive pulmonary disease (COPD) are limited. Thus, we performed a retrospective cohort study to optimize the use of immunotherapy in this special population. METHODS: We enrolled a total of 99 patients with advanced (stage IIIB/C-IV) NSCLC with comorbid COPD who had received immune checkpoint inhibitors (ICIs) according to the inclusion and exclusion criteria. They were divided into four groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline criteria as follows: no COPD group (n=19), mild COPD group (n=24), moderate COPD group (n=31), and severe COPD group (n=25). Routine blood, imaging characteristics, related cytokines including interleukin (IL)-6, IL-8, IL-10, etc., Krebs Von den Lungen (KL)-6, and corresponding indicators of immune-related adverse events (irAEs), incidence of irAEs, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were recorded and analyzed. Comparability of baseline factors above and clinical characteristics were evaluated. RESULTS: There were statistically significant differences in the incidence of irAEs among the four groups (P=0.003). The incidence of irAEs in patients with no COPD (n, 21.1%) and mild to moderate COPD (n, 8.3%, 32.3%) was lower than that in patients with severe COPD (n, 56.0%) (P=0.003). The median PFS of the mild to moderate COPD group was significantly longer than the severe COPD group (19.0 8.00 months, log-rank P=0.004). A significant increase of both ORR (P=0.004) and DCR (P=0.037), as well as higher IL-6 (P=0.000), IL-8 (P=0.026), and IL-10 (P=0.010) levels, have been observed in the mild to moderate COPD group compared with severe COPD group. IL-6 level was an independent factor influencing PFS [P=0.007, 95% confidence interval (95% CI): 1.000-1.002] and COPD grading was an independent predictor of irAEs (P=0.037, 95% CI: 1.035-3.039). CONCLUSIONS: Immunotherapy should be selected with caution for advanced NSCLC patients with comorbid severe COPD, considering the limited efficacy and the increased risk of immune-related adverse events related to the immune-checkpoint inhibitors administration in this special population.

73Immune-Related Diarrhea and Colitis in Non-small Cell Lung Cancers: Impact of Multidisciplinary Management in a Real-World Setting.PubMed

Laura Bonanno, Martina Lorenzi, Davide Massa, et al.
Oncologist. 2024 Jan 5;29(1):e118-e130. doi: 10.1093/oncolo/oyad238.
INTRODUCTION: Immune-related adverse events (irAEs) constitute a challenge in the clinical management of solid tumors. This study aims to collect real-world data on the occurrence of immune-mediated diarrhea and colitis (IMDC) in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs) and to assess the clinical impact of a multidisciplinary approach (MDA) on IMDC management. METHODS: We retrospectively collected data on patients with aNSCLC consecutively treated with ICIs, either as single agent or in combination with chemotherapy, between September 2013 and July 2022. Among patients developing IMDC, we conducted blinded revision of colonic biopsies and evaluated the clinical impact of the introduction of MDA through predefined indicators. RESULTS: Among the 607 patients included, 84 (13.8%) experienced IMDC. Pathological review highlighted a high prevalence of microscopic colitis (28%), with a collagenous pattern linked to longer symptoms duration (P = .01). IMDC occurred more frequently in females (P = .05) and PD-L1 expressors (P = .014) and was correlated with longer progression-free survival (17.0 vs 5.8, P < .001) and overall survival (28.3 vs 9.5, P < .001). The introduction of MDA was associated with increased employment of diagnostical tools such as fecal calprotectin test (P < .001), colonoscopy (P < .001), and gastroenterological evaluation (P = .017) and a significant decrease in both grade 3 conversion rate (P = .046) and recurrence after rechallenge (P = .016). Hospitalization rate dropped from 17.2% to 3.8% (P: ns). CONCLUSION: These findings highlight the clinical relevance of IMDC and support the incorporation of a MDA to optimize the clinical management of this irAE to improve patient care. Prospective validation has been planned.

74Unexpected serious aplastic anemia from PD-1 inhibitors: beyond what we know.PubMed

Marco Filetti, Raffaele Giusti, Arianna Di Napoli, et al.
Tumori. 2019 Dec;105(6):NP48-NP51. doi: 10.1177/0300891619856197. Epub 2019 Jun 21.
INTRODUCTION: The recent introduction of checkpoint inhibitor-based immunotherapy has revolutionized the treatment of advanced lung cancers, becoming standard of care in both first- and second-line treatment. New types of toxicity are emerging with the increasingly widespread use of these inhibitors. CASE PRESENTATION: We describe a case of aplastic anemia in a patient with stage IV non-small cell lung cancer after a single administration of nivolumab. CONCLUSIONS: Several similar case reports reported in literature show an increasing rate of toxicities from immunotherapy in this setting. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice.

75Neoadjuvant Camrelizumab for Non-Small Cell Lung Cancer: A Retrospective Multicenter, Real-World Study (CTONG2004).PubMed

Si-Yang Liu, Qixun Chen, Chengzhi Zhou, et al.
Cancer Immunol Immunother. 2023 Jul;72(7):2257-2265. doi: 10.1007/s00262-023-03412-8. Epub 2023 Mar 5.
BACKGROUND: Camrelizumab has shown encouraging efficacy in advanced non-small cell lung cancer (NSCLC), either as monotherapy or combined with chemotherapy. However, evidence of neoadjuvant camrelizumab for NSCLC remains lacking. METHODS: Patients with NSCLC treated with neoadjuvant camrelizumab-based therapy followed by surgery between December 2020 and September 2021 were retrospectively reviewed. Demographic and clinical data, details of neoadjuvant therapy and surgical information were retrieved. RESULTS: In this multicenter retrospective real-world study, 96 patients were included. Ninety-five patients (99.0%) received neoadjuvant camrelizumab combined with platinum-based chemotherapy, with a median of 2 cycles (range 1-6). The median interval from the last dose to surgery was 33 days (range 13-102 days). Seventy patients (72.9%) underwent minimally invasive surgery. Lobectomy was the most frequent surgical procedure (94 [97.9%]). The median estimated intraoperative blood loss was 100 mL (range 5-1200 mL), and the median operative time was 3.0 h (range 1.5-6.5 h). The R0 resection rate was 93.8%. Twenty-one patients (21.9%) experienced postoperative complications, with the most common being cough and pain (both 6 [6.3%]). The overall response rate was 77.1% (95% CI 67.4-85.0%), and the disease control rate was 93.8% (95% CI 86.9-97.7%). Twenty-six patients (27.1%, 95% CI 18.5-37.1%) had pathological complete response. Neoadjuvant treatment-related adverse events of grade ≥ 3 were reported in seven patients (7.3%), with the most frequent being abnormal liver enzymes (two [2.1%]). No treatment-related deaths were reported. CONCLUSION: The real-world data indicated that camrelizumab-based therapy had promising efficacy for NSCLC in the neoadjuvant setting, with manageable toxicities. Prospective studies investigating neoadjuvant camrelizumab are warranted.

76Analysis of thromboembolic events in patients with non-small cell lung cancer who received adjuvant chemotherapy: single-center real-world data.PubMed

Tae-Hwan Kim, Yong Won Choi, Hyun Woo Lee, et al.
Sci Rep. 2022 May 10;12(1):7646. doi: 10.1038/s41598-022-11631-9.
Thromboembolic events (TEEs) are common in cancer patients, with increased risk of TEE by chemotherapy in patients with lung cancer. However, TEEs in patients with non-small cell lung cancer (NSCLC) who received adjuvant chemotherapy have rarely been reported. This study retrospectively analyzed real-world data of 275 patients with NSCLC treated with adjuvant chemotherapy after surgery from October, 2005 to June, 2020, in a single institution. The incidence of TEEs during or within one year of completion of adjuvant chemotherapy was investigated, and factors related to TEEs were analyzed. TEEs were confirmed in nine patients (3.3%), without fatal event related to TEEs. None of the factors, including Khorana score, was significantly associated with the occurrence of TEEs. All patients with TEEs had pathologic stage IIB or higher and a history of smoking, except for one patient. In conclusion, TEEs occurred in a smaller proportion of patients with NSCLC treated with adjuvant chemotherapy in the real world compared with those treated with palliative chemotherapy in previous reports. Furthermore, prophylactic anticoagulation in patients with NSCLC receiving adjuvant chemotherapy may not be needed except for high-risk patients, although those patients should be informed about the possible risk of TEEs.

77Comorbidities in lung cancer.PubMed

Agata Ewa Dutkowska, Adam Antczak
Pneumonol Alergol Pol. 2016;84(3):186-92. doi: 10.5603/PiAP.2016.0022.
Comorbidity is the occurrence of concomitant disease in addition to an index disease of interest or the simultaneous occurrence of multiple diseases in an individual. Lung cancer is associated with age and smoking, and both age and smoking are strongly associated with comorbidity. Lung cancer is the most common malignancy in the world. Comorbidity, such as diseases of cardiovascular, pulmonary and other systems may influence prognosis in lung cancer as well as complicate its treatment. In this paper we tried to conclude the significance of the individual comorbidities in lung cancer and their impact on particular treatment method.

78Prognosis of stage I non-small cell lung cancer patients aged ≥ 80 years who were considered medically operable but received best supportive care alone.PubMed

Kosuke Kashiwabara, Shinji Fujii, Shinsuke Tsumura, et al.
Cancer Treat Res Commun. 2022;33:100642. doi: 10.1016/j.ctarc.2022.100642. Epub 2022 Sep 24.
INTRODUCTION: Some elderly stage I non-small cell lung cancer (NSCLC) patients may refuse both stereotactic body radiotherapy (SBRT) and surgery and may instead desire best supportive care (BSC) alone, despite having a medically operable condition. METHODS: We retrospectively evaluated the differences in the 3-year overall survival (3-year OS) rates among elderly stage I NSCLC patients aged ≥ 80 years who received surgery (OP group, n = 39), SBRT (RT group, n = 32) or BSC alone (BSC group, n = 28), stratifying the later groups according to those who were medically inoperable (MI subgroup) and those who were considered medically operable but refused surgery (MO subgroup). RESULTS: During a median 39.1-month follow-up period, 44 patients died. The 3-year OS rates were longer and higher in the MI-RT subgroup and the OP group than in the MI-BSC subgroup (67%, 89%, and 22%, respectively; p = 0.001). No differences in the 3-year OS rates were seen among the MO-RT subgroup, the MO-BSC subgroup, and the OP group (75%, 70%, and 89%, respectively; p = 0.164). However, a multivariate analysis identified a performance status (PS) score of 1-2 or a Charlson comorbidity index (CCI) score of ≥2, as well as stage IB disease and BSC, as independently increasing the risk of death. CONCLUSIONS: Elderly stage I NSCLC patients who were medically operable but who refused surgery and desire BSC alone should be encouraged to undergo SBRT unless they have a good PS and are otherwise in healthy condition.

79Effect of adherence to treatment guidelines on overall survival in elderly non-small-cell lung cancer patients.PubMed

Jonatan Lindqvist, Antti Jekunen, Eero Sihvo, et al.
Lung Cancer. 2022 Sep;171:9-17. doi: 10.1016/j.lungcan.2022.07.006. Epub 2022 Jul 15.
OBJECTIVES: Mean age at diagnosis of lung cancer is increasing with increasing age in Western populations. The present study was designed to evaluate the effect of adherence to first-line treatment guidelines on overall survival (OS) in elderly patients with non-small-cell lung cancer (NSCLC) and reasons for non-adherence to treatment guidelines. MATERIALS AND METHODS: All patients aged ≥ 65 years diagnosed with NSCLC in Ostrobothnia, Finland, during the years 2016 to 2020 were identified from hospital registries. Adherence of first-line treatment to contemporary treatment guidelines was analysed based on diagnosis, tumour stage and performance status (PS), as was the effect of adherence on OS. RESULTS: A review of hospital registries identified 238 NSCLC patients aged ≥ 65 years. Guideline adherence by stage decreased significantly with age, with 66.4% of patients aged 65 to 74 years, but only 33.3% of those aged > 80 years treated according to guidelines (p < 0.001). Other factors associated with non-adherence to guidelines included poor PS, frailty, and limited lung function. Of the patients with PS 0-2, 26.9% were under-treated according to guidelines. Reasons for under-treatment included comorbidities, decreased lung function, physician decision to reduce treatment intensity or recommend best supportive care, patient choice and PS decline before treatment initiation. Guideline adherence increased overall OS of elderly NSCLC patients in all stages. Elderly PS 2 patients appear to benefit from guideline adherence and active treatment. In contrast, active treatment did not benefit patients with PS 3-4. CONCLUSIONS: Guideline adherence was associated with increased OS in elderly NSCLC patients. Almost 10% of elderly and otherwise fit NSCLC patients were not treated according to guidelines and could have benefitted from more intensive treatment.

80Newly diagnosed non-small cell lung cancer with interstitial lung abnormality: Prevalence, characteristics, and prognosis.PubMed

Min Zhu, Jiawen Yi, Yanping Su, et al.
Thorac Cancer. 2023 Jul;14(19):1874-1882. doi: 10.1111/1759-7714.14935. Epub 2023 May 26.
BACKGROUND: Along with the improvement of lung cancer screening implementation, the identification of interstitial lung abnormality (ILA) is increasing. Currently, there is a limited description of the oncogenic status and ILA subtypes among newly diagnosed non-small cell lung cancer (NSCLC) patients with ILA in the Chinese population. This study aimed to investigate the prevalence, characteristics, oncogenic status and factors associated with overall survival (OS) among NSCLC patients with ILA. METHODS: A total of 765 newly diagnosed NSCLC cases at our hospital were reviewed and ILA was diagnosed according to the criteria of the Fleischner Society. The characteristics, clinical pathological features and OS of NSCLC patients with ILA were retrospectively analyzed. RESULTS: Of the 765 patients included in the study, 101 (13.2%) cases experienced ILA at the time of NSCLC diagnosis. Multivariate analysis revealed that ILA was more likely to be detected in NSCLC patients who were age ≥60 (OR 2.404, p = 0.001), male gender (OR 2.476, p = 0.004), and EGFR wild-type (OR 2.035, p = 0.007). Additionally, according to the multivariate Cox model, the presence of ILA in NSCLC patients was significantly associated with a shorter OS period than those without ILA (751 days vs. 445 days, HR 0.6, p = 0.001). Following analysis, it was determined that OS in patients with usual interstitial pneumonia (UIP) was shorter than in those without UIP (HR 1.82, p = 0.037). CONCLUSION: ILA is a common comorbidity among newly diagnosed NSCLC patients. We found that patients with EGFR wild-type NSCLC were more likely to develop ILA. The presence of ILA, especially UIP, was significantly associated with poor NSCLC prognosis.

81Diabetes mellitus and survival of non-small cell lung cancer patients after surgery: A comprehensive systematic review and meta-analysis.PubMed

Han-Yu Deng, Xi Zheng, Panpan Zha, et al.
Thorac Cancer. 2019 Mar;10(3):571-578. doi: 10.1111/1759-7714.12985. Epub 2019 Jan 31.
BACKGROUND: Diabetes mellitus (DM) is one of the most common comorbidities in surgically treated non-small cell lung cancer (NSCLC) patients and has a negative impact on short-term outcomes. However, the impact of DM on long-term survival of such patients remains controversial; therefore, we conducted a comprehensive updated meta-analysis. METHODS: We systematically searched relevant studies in PubMed, Embase, Cochrane Library, and Web of Science up to 6 September 2018. Hazard ratios (HRs) for the impact of DM on overall survival (OS) and recurrence-free survival (RFS) of patients with surgically treated NSCLC were extracted and analyzed using the STATA 12.0 package. RESULTS: We included 13 cohort studies consisting of 4343 patients (730 patients with DM and 3613 patients without) with surgically treated NSCLC. Meta-analysis showed that patients with DM had significantly poorer OS (random effects: HR 1.30, 95% confidence interval 1.05-1.60; P = 0.016) than those without. However, with a limited sample size, there was no significant difference in RFS (random effects: HR 1.06, 95% confidence interval 0.71-1.58; P = 0.786) between patients with and without DM after surgical resection of NSCLC. CONCLUSION: DM is an independent unfavorable prognostic factor for patients with surgically treated NSCLC. High-quality studies with appropriate adjustment for confounding factors are needed to confirm our conclusions.

82Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.PubMed

Robert Timmerman, Ronald McGarry, Constantin Yiannoutsos, et al.
J Clin Oncol. 2006 Oct 20;24(30):4833-9. doi: 10.1200/JCO.2006.07.5937.
PURPOSE: Surgical resection is standard therapy in stage I non-small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. PATIENTS AND METHODS: Eligible patients included clinically staged T1 or T2 (< or = 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. RESULTS: All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have died as a result of cancer (n = 5), treatment (n = 6), or comorbid illnesses (n = 17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in a total of 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors. CONCLUSION: High rates of local control are achieved with this SBRT regimen in medically inoperable patients with stage I NSCLC. Both local recurrence and toxicity occur late after this treatment. This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.

83The advanced lung cancer inflammation index is the optimal inflammatory biomarker of overall survival in patients with lung cancer.PubMed

Mengmeng Song, Qi Zhang, Chunhua Song, et al.
J Cachexia Sarcopenia Muscle. 2022 Oct;13(5):2504-2514. doi: 10.1002/jcsm.13032. Epub 2022 Jul 14.
BACKGROUNDS: Malnutrition and systemic inflammatory responses are associated with poor overall survival (OS) in lung cancer patients, but it remains unclear which biomarkers are better for predicting their prognosis. This study tried to determine the best one among the existing common nutrition/inflammation-based indicators of OS for patients with lung cancer. MATERIALS AND METHODS: There were 16 nutrition or systemic inflammation-based indicators included in this study. The cut-off points for the indicators were calculated using maximally selected rank statistics. The OS was evaluated using the Kaplan-Meier estimator, and univariate and multivariate Cox proportional hazard models were used to determine the relationship between the indicators and OS. A time-dependent receiver operating characteristic curves (time-ROC) and C-index were calculated to assess the predictive ability of the different indicators. RESULTS: There were 1772 patients with lung cancer included in this study. In univariate analysis, all 16 indicators were significantly associated with OS of the patients (all P < 0.001). Except for platelet-to-lymphocyte ratio, all other indicators were independent predictors of OS in multivariate analysis (all P < 0.05). Low advanced lung cancer inflammation index (ALI) was associated with higher mortality risk of lung cancer [hazard ratio, 1.30; 95% confidence interval (CI), 1.13-1.49]. The results of the time-AUC and C-index analyses indicated that the ALI (C-index: 0.611) had the best predictive ability on the OS in patients with lung cancer. In different sub-groups, the ALI was the best indicator for predicting the OS of lung cancer patients regardless of sex (C-index, 0.609 for men and 0.613 for women) or smoking status (C-index, 0.629 for non-smoker and 0.601 for smoker) and in patients aged <65 years (C-index, 0.613). However, the modified Glasgow prognostic score was superior to the other indicators in non-small cell lung cancer patients (C-index, 0.639) or patients aged ≥65 years (C-index, 0.610), and the glucose-to-lymphocyte ratio performed better prognostic ability in patients with small cell lung cancer (C-index, 0.601). CONCLUSIONS: The prognostic ability of the ALI is superior to the other inflammation/nutrition-based indicators for all patients with lung cancer.

84The inflammatory burden index is a superior systemic inflammation biomarker for the prognosis of non-small cell lung cancer.PubMed

Hailun Xie, Guotian Ruan, Lishuang Wei, et al.
J Cachexia Sarcopenia Muscle. 2023 Apr;14(2):869-878. doi: 10.1002/jcsm.13199. Epub 2023 Feb 28.
BACKGROUND: Systemic inflammation, the most representative tumour-host interaction, plays a crucial role in disease progression and prognosis in patients with non-small cell lung cancer (NSCLC). Few studies have compared the performance of existing haematological systemic inflammation biomarkers in predicting the prognosis of NSCLC patients. The purpose of this study was to compare the prognostic value of existing systemic inflammation biomarkers and determine the optimal systemic inflammation biomarker in patients with NSCLC through a multicentre prospective study. METHODS: The predictive accuracy of systemic inflammation biomarkers for prognostic assessment in NSCLC was assessed using C-statistics. Inter-group differences in survival were assessed using the log-rank test and visualized using the Kaplan-Meier method. A restricted cubic spline (RCS) curve was used to explore the association between the biomarkers and survival. Independent prognostic biomarkers for overall survival were determined using multivariable Cox proportional hazards regression analysis. Logistic regression analysis was used to determine independent predictors of 90-day outcomes, length of hospitalization, hospitalization expenses and cachexia. RESULTS: The inflammatory burden index (IBI) had the highest C-statistic for predicting the prognosis of patients with NSCLC, reaching 0.640 (0.617, 0.663). Patients with a high IBI had significantly worse outcomes than those with a low IBI (35.46% vs. 57.22%; log-rank P < 0.001). The IBI was also able to differentiate the prognosis of patients with NSCLC with the same pathological stage. The RCS curve showed an inverted L-shaped dose-response relationship between the IBI and survival of patients with NSCLC. Multivariable Cox proportional hazards regression analysis showed that a high IBI was an independent risk factor for death of patients with NSCLC (hazard ratio = 1.229, 95% confidence interval [CI]: 1.131-1.335, P < 0.001). A high IBI was an independent predictor of 90-day outcomes (odds ratio [OR] = 1.789, 95% CI: 1.489-2.151, P < 0.001), prolonged hospital stays (OR = 1.560, 95% CI: 1.256-1.938, P < 0.001), high hospitalization expenses (OR = 1.476, 95% CI: 1.195-1.822, P < 0.001) and cachexia (OR = 1.741, 95%CI = 1.374-2.207, P < 0.001) in patients with NSCLC. CONCLUSIONS: The IBI was independently associated with overall survival, 90-day outcomes, length of hospitalization, hospitalization expenses and cachexia in NSCLC patients. As an optimal systemic inflammation biomarker, the IBI has broad clinical application prospects in predicting the prognosis of patients with NSCLC.

85Assessing Different Approaches to Leveraging Historical Smoking Exposure Data to Better Select Lung Cancer Screening Candidates: A Retrospective Validation Study.PubMed

Daniel J Kats, Yosra Adie, Abdulhakim Tlimat, et al.
Nicotine Tob Res. 2021 Aug 4;23(8):1334-1340. doi: 10.1093/ntr/ntaa192.
INTRODUCTION: There is mounting interest in the use of risk prediction models to guide lung cancer screening. Electronic health records (EHRs) could facilitate such an approach, but smoking exposure documentation is notoriously inaccurate. While the negative impact of inaccurate EHR data on screening practices reliant on dichotomized age and smoking exposure-based criteria has been demonstrated, less is known regarding its impact on the performance of model-based screening. AIMS AND METHODS: Data were collected from a cohort of 37 422 ever-smokers between the ages of 55 and 74, seen at an academic safety-net healthcare system between 1999 and 2018. The National Lung Cancer Screening Trial (NLST) criteria, PLCOM2012 and LCRAT lung cancer risk prediction models were validated against time to lung cancer diagnosis. Discrimination (area under the receiver operator curve [AUC]) and calibration were assessed. The effect of substituting the last documented smoking variables with differentially retrieved "history conscious" measures was also determined. RESULTS: The PLCOM2012 and LCRAT models had AUCs of 0.71 (95% CI, 0.69 to 0.73) and 0.72 (95% CI, 0.70 to 0.74), respectively. Compared with the NLST criteria, PLCOM2012 had a significantly greater time-dependent sensitivity (69.9% vs. 64.5%, p < .01) and specificity (58.3% vs. 56.4%, p < .001). Unlike the NLST criteria, the performances of the PLCOM2012 and LCRAT models were not prone to historical variability in smoking exposure documentation. CONCLUSIONS: Despite the inaccuracies of EHR-documented smoking histories, leveraging model-based lung cancer risk estimation may be a reasonable strategy for screening, and is of greater value compared with using NLST criteria in the same setting. IMPLICATIONS: EHRs are potentially well suited to aid in the risk-based selection of lung cancer screening candidates, but healthcare providers and systems may elect not to leverage EHR data due to prior work that has shown limitations in structured smoking exposure data quality. Our findings suggest that despite potential inaccuracies in the underlying EHR data, screening approaches that use multivariable models may perform significantly better than approaches that rely on simpler age and exposure-based criteria. These results should encourage providers to consider using pre-existing smoking exposure data with a model-based approach to guide lung cancer screening practices.

86Woman-centred care and integrated electronic medical records within Australian maternity settings: Point prevalence audit and observational study.PubMed

Lauren Kearney, Alison Craswell, Roni Cole, et al.
Midwifery. 2023 Aug;123:103718. doi: 10.1016/j.midw.2023.103718. Epub 2023 May 12.
OBJECTIVE: Transition to paperless records brings new challenges to midwifery practice across the continuum of woman-centred care. There is limited and conflicting evidence on the relative benefits of electronic medical records in maternity settings. This article aims to inform the use of integrative electronic medical records within the maternity services' environment with attention to the midwife-woman relationship. DESIGN: This descriptive two-part study includes 1) an audit of electronic records in the early period following implementation (2-time points); and 2) an observational study to observe midwives' practice relating to electronic record use. SETTING: Two regional tertiary public hospitals PARTICIPANTS: Midwives providing care for childbearing women across antenatal, intrapartum and postnatal areas. FINDINGS: 400 integrated electronic medical records were audited for completeness. Most fields had high levels of complete data in the correct location. However, between time 1 (T1) and time 2 (T2), persistent missing data (foetal heart rate documented 30 minutely T1 36%; T2 42%), and incomplete or incorrectly located data (pathology results T1:63%; T2 54%; perineal repair T1 60%; T2 46%) were identified. Observationally, midwives were actively engaged with the integrative electronic medical record between 23% to 68% (median 46%; IQR 16) of the time. CONCLUSION: Midwives spent a significant amount of time completing documentation during clinical episodes of care. Largely, this documentation was found to be accurate, yet exceptions to data completeness, precision and location remained, indicating some concerns with software usability. IMPLICATIONS FOR PRACTICE: Time-intensive monitoring and documentation may hinder woman-centred midwifery care.

87Assessing the feasibility and external validity of natural language processing-extracted data for advanced lung cancer patients.PubMed

Yuchen Li, Jennifer Law, Lisa W Le, et al.
Lung Cancer. 2025 Jan;199:108080. doi: 10.1016/j.lungcan.2025.108080. Epub 2025 Jan 4.
BACKGROUND: Manual extraction of real-world clinical data for research can be time-consuming and prone to error. We assessed the feasibility of using natural language processing (NLP), an AI technique, to automate data extraction for patients with advanced lung cancer (aLC). We assessed the external validity of our NLP-extracted data by comparing our findings to those reported in the literature. METHODS: Patients diagnosed with stage IIIB or IV lung cancer between January 2015 to December 2017 at Princess Margaret Cancer Centre who received at least one dose of systemic therapy were included. Their electronic health records were provided to Pentavere's NLP platform, DARWEN, in March 2019. Descriptive statistics summarized baseline patient and cancer characteristics, molecular biomarkers, and first-line systemic therapies. Cox multivariate models were used to evaluate prognostic factors for advanced non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) cohort. RESULT: NLP extracted clinical information (n = 333 patients) in a total of 8 hours, with only a few missing data for smoking status (n = 2), and Eastern Cooperative Oncology Group (ECOG) status (n = 5). Baseline patient and cancer characteristics summarized from NLP-extracted data were comparable to those in previous studies and population reports. For NSCLC patients, being male (HR 1.44, 95 % CI [1.04, 2.00]), having worse ECOG (1.48 [1.22, 1.81]), and having liver (2.24 [1.45, 3.46]), bone (2.09 [1.48, 2.96]), or lung metastases (2.54 [1.05, 2.26]) were associated with worse survival outcomes. For SCLC patients, having older age (HR 1.70 per 10 years, 95 % CI [1.10, 2.63]) and liver metastases (3.81 [1.61, 9.01]) were associated with worse survival outcomes. CONCLUSION: Our study demonstrated that automated data extraction using NLP is feasible and time efficient. Additionally, the NLP-extracted data can be used to identify valid and useful clinical endpoints for research. NLP holds significant potential to accelerate the extraction of real-world data for future observational studies.

88Generating Real-World Tumor Burden Endpoints from Electronic Health Record Data: Comparison of RECIST, Radiology-Anchored, and Clinician-Anchored Approaches for Abstracting Real-World Progression in Non-Small Cell Lung Cancer.PubMed

Sandra D Griffith, Melisa Tucker, Bryan Bowser, et al.
Adv Ther. 2019 Aug;36(8):2122-2136. doi: 10.1007/s12325-019-00970-1. Epub 2019 May 28.
INTRODUCTION: Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are standard clinical trial metrics. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. METHODS: In this retrospective study, cohorts were randomly selected from Flatiron Health's database of de-identified patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach tested for feasibility (N = 26). Three non-RECIST approaches were tested for feasibility, reliability, and validity (N = 200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. Qualitative and quantitative methods were used. RESULTS: A RECIST-based approach was not feasible: cancer progression could be ascertained for 23% (6/26 patients). Radiology- and clinician-anchored approaches identified at least one rwP event for 87% (173/200 patients). rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months [95% confidence interval (CI) 14, 19]. Median real-world progression-free survival (rwPFS) was 5.5 months (95% CI 4.6, 6.3) and 4.9 months (95% CI 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman's rho 0.65-0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. CONCLUSIONS: RECIST cannot adequately assess cancer progression in EHR-derived data because of missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data. FUNDING: Flatiron Health Inc., which is an independent subsidiary of the Roche group.

89Privacy-Preserving Record Linkage of Deidentified Records Within a Public Health Surveillance System: Evaluation Study.PubMed

Long Nguyen, Mark Stoové, Douglas Boyle, et al.
J Med Internet Res. 2020 Jun 24;22(6):e16757. doi: 10.2196/16757.
BACKGROUND: The Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) was established to monitor national testing and test outcomes for blood-borne viruses (BBVs) and sexually transmissible infections (STIs) in key populations. ACCESS extracts deidentified data from sentinel health services that include general practice, sexual health, and infectious disease clinics, as well as public and private laboratories that conduct a large volume of BBV/STI testing. An important attribute of ACCESS is the ability to accurately link individual-level records within and between the participating sites, as this enables the system to produce reliable epidemiological measures. OBJECTIVE: The aim of this study was to evaluate the use of GRHANITE software in ACCESS to extract and link deidentified data from participating clinics and laboratories. GRHANITE generates irreversible hashed linkage keys based on patient-identifying data captured in the patient electronic medical records (EMRs) at the site. The algorithms to produce the data linkage keys use probabilistic linkage principles to account for variability and completeness of the underlying patient identifiers, producing up to four linkage key types per EMR. Errors in the linkage process can arise from imperfect or missing identifiers, impacting the system's integrity. Therefore, it is important to evaluate the quality of the linkages created and evaluate the outcome of the linkage for ongoing public health surveillance. METHODS: Although ACCESS data are deidentified, we created two gold-standard datasets where the true match status could be confirmed in order to compare against record linkage results arising from different approaches of the GRHANITE Linkage Tool. We reported sensitivity, specificity, and positive and negative predictive values where possible and estimated specificity by comparing a history of HIV and hepatitis C antibody results for linked EMRs. RESULTS: Sensitivity ranged from 96% to 100%, and specificity was 100% when applying the GRHANITE Linkage Tool to a small gold-standard dataset of 3700 clinical medical records. Medical records in this dataset contained a very high level of data completeness by having the name, date of birth, post code, and Medicare number available for use in record linkage. In a larger gold-standard dataset containing 86,538 medical records across clinics and pathology services, with a lower level of data completeness, sensitivity ranged from 94% to 95% and estimated specificity ranged from 91% to 99% in 4 of the 6 different record linkage approaches. CONCLUSIONS: This study's findings suggest that the GRHANITE Linkage Tool can be used to link deidentified patient records accurately and can be confidently used for public health surveillance in systems such as ACCESS.

90Accounting for Delayed Entry in Analyses of Overall Survival in Clinico-Genomic Databases.PubMed

Daniel Backenroth, Jeremy Snider, Ronglai Shen, et al.
Cancer Epidemiol Biomarkers Prev. 2022 Jun 1;31(6):1195-1201. doi: 10.1158/1055-9965.EPI-21-0876.
BACKGROUND: Clinico-genomic databases favor inclusion of long-term survivors, leading to potentially biased overall survival (OS) analyses. Risk set adjustments relying on the independent delayed entry assumption may mitigate this bias. We aimed to determine whether this assumption is satisfied in a dataset of patients with advanced non-small cell lung cancer (aNSCLC), and to give guidance for clinico-genomic OS analyses when the assumption is not satisfied. METHODS: We analyzed the association of timing of next-generation sequencing (NGS) testing with real-world OS (rwOS) in patient data from a United States-based nationwide longitudinal deidentified electronic health records-derived database. Estimates of rwOS using risk set adjustment were compared with estimates computed with respect to all patients, regardless of NGS testing. RESULTS: The independent delayed entry assumption was not satisfied in this database, and later sequencing had a negative association with the hazard of death after sequencing. In a model adjusted for relevant characteristics, each month delay in sequencing was associated with a 2% increase in the hazard of death. However, until the median survival time, estimates of OS using risk set adjustment are similar to estimates computed for all patients, regardless of NGS testing. CONCLUSIONS: rwOS analyses in clinico-genomic databases should assess the independent delayed entry assumption. Comparisons versus broader population may be useful to evaluate the rwOS differences between calculations using risk set adjustment and patient cohorts where the bias relates to overrepresentation of long survivors. IMPACT: This study illustrates practices that can increase the interpretability of findings from OS analyses in clinico-genomic databases.

91Prevalence of Missing Data in the National Cancer Database and Association With Overall Survival.PubMed

Daniel X Yang, Rohan Khera, Joseph A Miccio, et al.
JAMA Netw Open. 2021 Mar 1;4(3):e211793. doi: 10.1001/jamanetworkopen.2021.1793.
IMPORTANCE: Cancer registries are important real-world data sources consisting of data abstraction from the medical record; however, patients with unknown or missing data are underrepresented in studies that use such data sources. OBJECTIVE: To assess the prevalence of missing data and its association with overall survival among patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, all variables within the National Cancer Database were reviewed for missing or unknown values for patients with the 3 most common cancers in the US who received diagnoses from January 1, 2006, to December 31, 2015. The prevalence of patient records with missing data and the association with overall survival were assessed. Data analysis was performed from February to August 2020. EXPOSURES: Any missing data field within a patient record among 63 variables of interest from more than 130 total variables in the National Cancer Database. MAIN OUTCOMES AND MEASURES: Prevalence of missing data in the medical records of patients with cancer and associated 2-year overall survival. RESULTS: A total of 1 198 749 patients with non-small cell lung cancer (mean [SD] age, 68.5 [10.9] years; 628 811 men [52.5%]), 2 120 775 patients with breast cancer (mean [SD] age, 61.0 [13.3] years; 2 101 758 women [99.1%]), and 1 158 635 patients with prostate cancer (mean [SD] age, 65.2 [9.0] years; 100% men) were included in the analysis. Among those with non-small cell lung cancer, 851 295 patients (71.0%) were missing data for variables of interest; 2-year overall survival was 33.2% for patients with missing data and 51.6% for patients with complete data (P < .001). Among those with breast cancer, 1 161 096 patients (54.7%) were missing data for variables of interest; 2-year overall survival was 93.2% for patients with missing data and 93.9% for patients with complete data (P < .001). Among those with prostate cancer, 460 167 patients (39.7%) were missing data for variables of interest; 2-year overall survival was 91.0% for patients with missing data and 95.6% for patients with complete data (P < .001). CONCLUSIONS AND RELEVANCE: This study found that within a large cancer registry-based real-world data source, there was a high prevalence of missing data that were unable to be ascertained from the medical record. The prevalence of missing data among patients with cancer was associated with heterogeneous differences in overall survival. Improvements in documentation and data quality are necessary to make optimal use of real-world data for clinical advancements.

92Development and Validation of a High-Quality Composite Real-World Mortality Endpoint.PubMed

Melissa D Curtis, Sandra D Griffith, Melisa Tucker, et al.
Health Serv Res. 2018 Dec;53(6):4460-4476. doi: 10.1111/1475-6773.12872. Epub 2018 May 14.
OBJECTIVE: To create a high-quality electronic health record (EHR)-derived mortality dataset for retrospective and prospective real-world evidence generation. DATA SOURCES/STUDY SETTING: Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index (NDI). STUDY DESIGN: We developed a recent, linkable, high-quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI. Data quality of the mortality variable version 2.0 is reported here. PRINCIPAL FINDINGS: For advanced non-small-cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI. For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan-Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI-based estimates. CONCLUSIONS: For EHR-derived data to yield reliable real-world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI.

93An evaluation of the impact of missing deaths on overall survival analyses of advanced non-small cell lung cancer patients conducted in an electronic health records database.PubMed

Gillis Carrigan, Samuel Whipple, Michael D Taylor, et al.
Pharmacoepidemiol Drug Saf. 2019 May;28(5):572-581. doi: 10.1002/pds.4758. Epub 2019 Mar 14.
PURPOSE: The aim of this study was to assess the impact of missing death data on survival analyses conducted in an oncology EHR-derived database. METHODS: The study was conducted using the Flatiron Health oncology database and the National Death Index (NDI) as a gold standard. Three analytic frameworks were evaluated in advanced non-small cell lung cancer (aNSCLC) patients: median overall survival [mOS]), relative risk estimates conducted within the EHR-derived database, and "external control arm" analyses comparing an experimental group augmented with mortality data from the gold standard to a control group from the EHR-derived database only. The hazard ratios (HRs) obtained within the EHR-derived database (91% sensitivity) and the external control arm analyses, were compared with results when both groups were augmented with mortality data from the gold standard. The above analyses were repeated using simulated lower mortality sensitivities to understand the impact of more extreme levels of missing deaths. RESULTS: Bias in mOS ranged from modest (0.6-0.9 mos.) in the EHR-derived cohort with (91% sensitivity) to substantial when lower sensitivities were generated through simulation (3.3-9.7 mos.). Overall, small differences were observed in the HRs for the EHR-derived cohort across comparative analyses when compared with HRs obtained using the gold standard data source. When only one treatment arm was subject to estimation bias, the bias was slightly more pronounced, but increased substantially when lower sensitivities were simulated. CONCLUSIONS: The impact on survival analysis is minimal with high mortality sensitivity with only modest impact associated within external control arm applications.

94Differential frequency in imaging-based outcome measurement: Bias in real-world oncology comparative-effectiveness studies.PubMed

Blythe J S Adamson, Xinran Ma, Sandra D Griffith, et al.
Pharmacoepidemiol Drug Saf. 2022 Jan;31(1):46-54. doi: 10.1002/pds.5323. Epub 2021 Jul 21.
BACKGROUND: Comparative-effectiveness studies using real-world data (RWD) can be susceptible to surveillance bias. In solid tumor oncology studies, analyses of endpoints such as progression-free survival (PFS) are based on progression events detected by imaging assessments. This study aimed to evaluate the potential bias introduced by differential imaging assessment frequency when using electronic health record (EHR)-derived data to investigate the comparative effectiveness of cancer therapies. METHODS: Using a nationwide de-identified EHR-derived database, we first analyzed imaging assessment frequency patterns in patients diagnosed with advanced non-small cell lung cancer (aNSCLC). We used those RWD inputs to develop a discrete event simulation model of two treatments where disease progression was the outcome and PFS was the endpoint. Using this model, we induced bias with differential imaging assessment timing and quantified its effect on observed versus true treatment effectiveness. We assessed percent bias in the estimated hazard ratio (HR). RESULTS: The frequency of assessments differed by cancer treatment types. In simulated comparative-effectiveness studies, PFS HRs estimated using real-world imaging assessment frequencies differed from the true HR by less than 10% in all scenarios (range: 0.4% to -9.6%). The greatest risk of biased effect estimates was found comparing treatments with widely different imaging frequencies, most exaggerated in disease settings where time to progression is very short. CONCLUSIONS: This study provided evidence that the frequency of imaging assessments to detect disease progression can differ by treatment type in real-world patients with cancer and may induce some bias in comparative-effectiveness studies in some situations.

95Bias in pharmacoepidemiologic studies using secondary health care databases: a scoping review.PubMed

Guillermo Prada-Ramallal, Bahi Takkouche, Adolfo Figueiras
BMC Med Res Methodol. 2019 Mar 11;19(1):53. doi: 10.1186/s12874-019-0695-y.
BACKGROUND: The availability of clinical and therapeutic data drawn from medical records and administrative databases has entailed new opportunities for clinical and epidemiologic research. However, these databases present inherent limitations which may render them prone to new biases. We aimed to conduct a structured review of biases specific to observational clinical studies based on secondary databases, and to propose strategies for the mitigation of those biases. METHODS: Scoping review of the scientific literature published during the period 2000-2018 through an automated search of MEDLINE, EMBASE and Web of Science, supplemented with manually cross-checking of reference lists. We included opinion essays, methodological reviews, analyses or simulation studies, as well as letters to the editor or retractions, the principal objective of which was to highlight the existence of some type of bias in pharmacoepidemiologic studies using secondary databases. RESULTS: A total of 117 articles were included. An increasing trend in the number of publications concerning the potential limitations of secondary databases was observed over time and across medical research disciplines. Confounding was the most reported category of bias (63.2% of articles), followed by selection and measurement biases (47.0% and 46.2% respectively). Confounding by indication (32.5%), unmeasured/residual confounding (28.2%), outcome misclassification (28.2%) and "immortal time" bias (25.6%) were the subcategories most frequently mentioned. CONCLUSIONS: Suboptimal use of secondary databases in pharmacoepidemiologic studies has introduced biases in the studies, which may have led to erroneous conclusions. Methods to mitigate biases are available and must be considered in the design, analysis and interpretation phases of studies using these data sources.

96Addressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer.PubMed

Sanjay Popat, Stephen V Liu, Nicolas Scheuer, et al.
Nat Commun. 2022 Jun 17;13(1):3500. doi: 10.1038/s41467-022-30908-1.
As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided into rare oncogene-driven subsets, conducting randomised trials becomes challenging. Using real-world data (RWD) to construct control arms for single-arm trials provides an option for comparative data. However, non-randomised treatment comparisons have the potential to be biased and cause concern for decision-makers. Using the example of pralsetinib from a RET fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative survival benefit when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. Quantitative bias analyses show that results for the RWD-trial comparisons are robust to data missingness, potential poorer outcomes in RWD and residual confounding. Overall, the study provides evidence in favour of pralsetinib as a first-line treatment for RET fusion-positive aNSCLC. The quantification of potential bias performed in this study can be used as a template for future studies of this nature.

97Quantitative bias analysis for external control arms using real-world data in clinical trials: a primer for clinical researchers.PubMed

Kristian Thorlund, Stephen Duffield, Sanjay Popat, et al.
J Comp Eff Res. 2024 Mar;13(3):e230147. doi: 10.57264/cer-2023-0147. Epub 2024 Jan 11.
Development of medicines in rare oncologic patient populations are growing, but well-powered randomized controlled trials are typically extremely challenging or unethical to conduct in such settings. External control arms using real-world data are increasingly used to supplement clinical trial evidence where no or little control arm data exists. The construction of an external control arm should always aim to match the population, treatment settings and outcome measurements of the corresponding treatment arm. Yet, external real-world data is typically fraught with limitations including missing data, measurement error and the potential for unmeasured confounding given a nonrandomized comparison. Quantitative bias analysis (QBA) comprises a collection of approaches for modelling the magnitude of systematic errors in data which cannot be addressed with conventional statistical adjustment. Their applications can range from simple deterministic equations to complex hierarchical models. QBA applied to external control arm represent an opportunity for evaluating the validity of the corresponding comparative efficacy estimates. We provide a brief overview of available QBA approaches and explore their application in practice. Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1-2% among all NSCLC), we illustrate how QBA can be applied to external control arms. We illustrate how QBA is used to ascertain robustness of results despite a large proportion of missing data on baseline ECOG performance status and suspicion of unknown confounding. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several 'tipping-point' scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided.

98Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.PubMed

Christen Gray, Eleanor Ralphs, Matthew P Fox, et al.
Pharmacoepidemiol Drug Saf. 2024 May;33(5):e5796. doi: 10.1002/pds.5796.
PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

99Assessment of Alectinib vs Ceritinib in ALK-Positive Non-Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data.PubMed

Samantha Wilkinson, Alind Gupta, Nicolas Scheuer, et al.
JAMA Netw Open. 2021 Oct 1;4(10):e2126306. doi: 10.1001/jamanetworkopen.2021.26306.
IMPORTANCE: Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). OBJECTIVE: To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021. EXPOSURES: Initiation of alectinib or ceritinib therapy. MAIN OUTCOMES AND MEASURES: The main outcome was OS. RESULTS: In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD. CONCLUSIONS AND RELEVANCE: Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.